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Fang X, Song T, Zheng L, Weng Y, Gao F, Mo C, Zheng X. Targeting mast cell activation alleviates anti-MHC I antibody and LPS-induced TRALI in mice by pharmacologically blocking the TLR3 and MAPK pathway. Biomed Pharmacother 2024; 180:117456. [PMID: 39326104 DOI: 10.1016/j.biopha.2024.117456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/10/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Transfusion-related lung injury (TRALI) poses a significant risk following blood transfusion and remains the primary cause of transfusion-related morbidity and mortality, primarily driven by the activation of immune cells through anti-major histocompatibility complex class I (anti-MHC I) antibody. However, it remains to be defined how immune microenvironmental cue contributes to TRALI. Here, we uncover that activated mast cells within the immune microenvironment promote lung inflammation and injury in antibody-mediated TRALI, both in vitro and in vivo. This was demonstrated by co-culturing lipopolysaccharide (LPS)-pretreated mast cell line with anti-MHC I antibody and establishing a "two-hit" TRALI mouse model through intratracheal injection of LPS followed by tail-vein injection of anti-MHC I antibody. Importantly, mast cell-deficient KitW-sh/W-sh mice exhibited markedly reduced lung inflammation and injury responses in antibody-mediated TRALI compared with wild-type mice. Mechanistically, activation of toll-like receptor 3 (TLR3)/mitogen-activated protein kinase (MAPK) signaling pathway in mast cells contributes to the enhanced production of proinflammatory factors. These excessive proinflammatory factors produced by activated mast cells contribute to lung inflammation and injury in antibody-mediated TRALI. Pharmacologically targeting the TLR3/MAPK pathway to inhibit mast cell activation normalizes the proinflammatory microenvironment and alleviates lung inflammation and injury in the preclinical TRALI mouse model. Overall, we find that activation of mast cells via the TLR3/MAPK pathway contributes to lung inflammation and injury in antibody-mediated TRALI, providing novel insights into its underlying mechanisms. Furthermore, targeting activated mast cells and the associated pathway offers potential therapeutic strategies for antibody-mediated TRALI.
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Affiliation(s)
- Xiaobin Fang
- Department of Anesthesiology/Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, China.
| | - Tianjiao Song
- Department of Emergency, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Key Laboratory of Emergency Medicine, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, China
| | - Ling Zheng
- Department of Anesthesiology/Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, China
| | - Yueyi Weng
- Department of Anesthesiology/Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, China
| | - Fei Gao
- Department of Anesthesiology/Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, China
| | - Chunheng Mo
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
| | - Xiaochun Zheng
- Department of Anesthesiology/Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, China; Department of Anesthesiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University & Fujian Emergency Medical Center, Fujian Provincial Key Laboratory of Emergency Medicine, Fujian Provincial Key Laboratory of Critical Medicine, Fujian Provincial Co-constructed Laboratory of "Belt and Road", Fuzhou, Fujian, China.
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Shan F, Tang F, Liu Y, Han X, Wu W, Tang Y, Zhan Q, Zhang N. The effect of adoptive transferring myeloid-derived suppressor cells in ventilator-induced lung injury mice. Heliyon 2024; 10:e25595. [PMID: 38356581 PMCID: PMC10865327 DOI: 10.1016/j.heliyon.2024.e25595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/16/2024] Open
Abstract
The effects of adoptive transferring myeloid-derived suppressor cells (MDSCs) to mice with ventilator-induced lung injury (VILI) are unclear. Our objective was to investigate the effects of adoptively transferring MDSCs in VILI. The mouse model was created by introducing mechanical ventilation through a high tidal volume of 20 ml/kg for 4 h. Inflammation-induced MDSCs (iMDSCs) were collected from the bone marrow of mice with cecal ligation and puncture. iMDSCs were administrated through retrobulbar angular vein 1 h before the mechanical ventilation. The control group was anesthetized and maintained spontaneous respiration. After the termination of mechanical ventilation, bronchoalveolar lavage fluid (BALF) and lung samples 6 h were collected. The concentrations of BALF protein, levels of inflammatory mediators, and white blood cells were all significantly decreased in mice treated with iMDSCs. Histological examinations indicated reduced lung damage after iMDSCs treatment. Moreover, adoptive transfer of iMDSCs could reduce CD4+ T-cell counts and inhibit its inflammatory cytokine secretion. iMDSCs treatment was found to had no immunostimulatory effects or cause secondary infections in mice. In conclusion, MDSCs might be a potential targeted therapy for alleviating the inflammatory response of VILI mice in a T-cell dependent manner.
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Affiliation(s)
- Fangzhen Shan
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Shandong, China
- Medical Research Center, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Fenglian Tang
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Yuan Liu
- Department of Intensive care unit III, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Xiao Han
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Wei Wu
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Yanhua Tang
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Shandong, China
| | - Qingyuan Zhan
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Nannan Zhang
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Jining Medical University, Shandong, China
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
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Spadaro S, Jimenez-Santana JD, La Rosa R, Spinazzola G, Argente Navarro P, Volta CA, Scaramuzzo G. Prone Positioning and Molecular Biomarkers in COVID and Non-COVID ARDS: A Narrative Review. J Clin Med 2024; 13:317. [PMID: 38256451 PMCID: PMC10816213 DOI: 10.3390/jcm13020317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/25/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
Prone positioning (PP) represents a therapeutic intervention with the proven capacity of ameliorating gas exchanges and ventilatory mechanics indicated in acute respiratory distress syndrome (ARDS). When PP is selectively applied to moderate-severe cases of ARDS, it sensitively affects clinical outcomes, including mortality. After the COVID-19 outbreak, clinical application of PP peaked worldwide and was applied in 60% of treated cases, according to large reports. Research on this topic has revealed many physiological underpinnings of PP, focusing on regional ventilation redistribution and the reduction of parenchymal stress and strain. However, there is a lack of evidence on biomarkers behavior in different phases and phenotypes of ARDS. Patients response to PP are, to date, decided on PaO2/FiO2 ratio improvement, whereas scarce data exist on biomarker tracking during PP. The purpose of this review is to explore current evidence on the clinical relevance of biomarkers in the setting of moderate-severe ARDS of different etiologies (i.e., COVID and non-COVID-related ARDS). Moreover, this review focuses on how PP may modulate biomarkers and which biomarkers may have a role in outcome prediction in ARDS patients.
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Affiliation(s)
- Savino Spadaro
- Department of Translational Medicine, University of Ferrara, 44124 Ferrara, Italy; (R.L.R.); (C.A.V.); (G.S.)
- Anesthesia and Intensive Care Unit, Emergency Department, Azienda Ospedaliera Universitaria di Ferrara, 44124 Ferrara, Italy
| | - Jose Daniel Jimenez-Santana
- Department of Anaesthesiology, Hospital Universitari i Politécnic la Fe, 46026 Valencia, Spain; (J.D.J.-S.); (P.A.N.)
| | - Riccardo La Rosa
- Department of Translational Medicine, University of Ferrara, 44124 Ferrara, Italy; (R.L.R.); (C.A.V.); (G.S.)
- Anesthesia and Intensive Care Unit, Emergency Department, Azienda Ospedaliera Universitaria di Ferrara, 44124 Ferrara, Italy
| | - Giorgia Spinazzola
- Department of Emergency, Anesthesiologic and Reanimation Sciences, Fondazione Policlinico Universitario Gemelli, IRCSS, 00168 Rome, Italy;
| | - Pilar Argente Navarro
- Department of Anaesthesiology, Hospital Universitari i Politécnic la Fe, 46026 Valencia, Spain; (J.D.J.-S.); (P.A.N.)
| | - Carlo Alberto Volta
- Department of Translational Medicine, University of Ferrara, 44124 Ferrara, Italy; (R.L.R.); (C.A.V.); (G.S.)
- Anesthesia and Intensive Care Unit, Emergency Department, Azienda Ospedaliera Universitaria di Ferrara, 44124 Ferrara, Italy
| | - Gaetano Scaramuzzo
- Department of Translational Medicine, University of Ferrara, 44124 Ferrara, Italy; (R.L.R.); (C.A.V.); (G.S.)
- Anesthesia and Intensive Care Unit, Emergency Department, Azienda Ospedaliera Universitaria di Ferrara, 44124 Ferrara, Italy
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Safety and Outcomes of Prolonged Usual Care Prone Position Mechanical Ventilation to Treat Acute Coronavirus Disease 2019 Hypoxemic Respiratory Failure. Crit Care Med 2021; 49:490-502. [PMID: 33405409 DOI: 10.1097/ccm.0000000000004818] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Prone position ventilation is a potentially life-saving ancillary intervention but is not widely adopted for coronavirus disease 2019 or acute respiratory distress syndrome from other causes. Implementation of lung-protective ventilation including prone positioning for coronavirus disease 2019 acute respiratory distress syndrome is limited by isolation precautions and personal protective equipment scarcity. We sought to determine the safety and associated clinical outcomes for coronavirus disease 2019 acute respiratory distress syndrome treated with prolonged prone position ventilation without daily repositioning. DESIGN Retrospective single-center study. SETTING Community academic medical ICU. PATIENTS Sequential mechanically ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. INTERVENTIONS Lung-protective ventilation and prolonged protocolized prone position ventilation without daily supine repositioning. Supine repositioning was performed only when Fio2 less than 60% with positive end-expiratory pressure less than 10 cm H2O for greater than or equal to 4 hours. MEASUREMENTS AND MAIN RESULTS Primary safety outcome: proportion with pressure wounds by Grades (0-4). Secondary outcomes: hospital survival, length of stay, rates of facial and limb edema, hospital-acquired infections, device displacement, and measures of lung mechanics and oxygenation. Eighty-seven coronavirus disease 2019 patients were mechanically ventilated. Sixty-one were treated with prone position ventilation, whereas 26 did not meet criteria. Forty-two survived (68.9%). Median (interquartile range) time from intubation to prone position ventilation was 0.28 d (0.11-0.80 d). Total prone position ventilation duration was 4.87 d (2.08-9.97 d). Prone position ventilation was applied for 30.3% (18.2-42.2%) of the first 28 days. Pao2:Fio2 diverged significantly by day 3 between survivors 147 (108-164) and nonsurvivors 107 (85-146), mean difference -9.632 (95% CI, -48.3 to 0.0; p = 0·05). Age, driving pressure, day 1, and day 3 Pao2:Fio2 were predictive of time to death. Thirty-eight (71.7%) developed ventral pressure wounds that were associated with prone position ventilation duration and day 3 Sequential Organ Failure Assessment. Limb weakness occurred in 58 (95.1%) with brachial plexus palsies in five (8.2%). Hospital-acquired infections other than central line-associated blood stream infections were infrequent. CONCLUSIONS Prolonged prone position ventilation was feasible and relatively safe with implications for wider adoption in treating critically ill coronavirus disease 2019 patients and acute respiratory distress syndrome of other etiologies.
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Singh RK, Najmi AK. Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory Disorders. Curr Drug Targets 2020; 20:367-379. [PMID: 30112991 DOI: 10.2174/1389450119666180816121323] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 07/17/2018] [Accepted: 08/09/2018] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The primary focus of this review is to highlight the current and emerging proinflammatory role of MK2 kinase signaling in p38MAPK pathway and to provide a detailed evaluation on the prospects of MK2 inhibition with special emphasis on the etiology of chronic inflammatory airway diseases, such as asthma, idiopathic pulmonary fibrosis, lung cancer, acute lung injury and acute respiratory distress syndrome. BACKGROUND MK2 belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a critical factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins. Targeted inhibition of MK2 kinase has been shown to significantly reduce the production and release of these cytokine molecules. Therefore, MK2 has been identified as an effective strategy (alternative to p38MAPK) to block this pro-inflammatory signaling pathway. RESULTS The inhibition of MK2 may lead to similar or better efficacy as that of p38 inhibitors, and interestingly avoids the systemic toxicity shown by the p38 inhibitors. Thus, MK2 has been the focus of intense interdisciplinary research and its specific inhibition can be a novel and potential therapeutic strategy for the treatment of chronic airway inflammatory diseases. CONCLUSION Promising advancement in understanding and rigorous exploration of the role of MK2 kinase in inflammatory processes may contribute to the development of newer and safer therapy for the treatment of chronic airway inflammatory diseases in the future.
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Affiliation(s)
- Rakesh Kumar Singh
- School of Pharmaceutical Sciences, Apeejay Stya University, Sohna, Gurgaon-122013, India.,Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India
| | - Abul Kalam Najmi
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India
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Bos LDJ, Scicluna BP, Ong DSY, Cremer O, van der Poll T, Schultz MJ. Understanding Heterogeneity in Biologic Phenotypes of Acute Respiratory Distress Syndrome by Leukocyte Expression Profiles. Am J Respir Crit Care Med 2020; 200:42-50. [PMID: 30645145 DOI: 10.1164/rccm.201809-1808oc] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Rationale: Two biologic phenotypes of acute respiratory distress syndrome (ARDS) have been identified based on plasma protein markers in four previous studies. Objectives: To determine if blood leukocyte gene expression is different between the "reactive" and "uninflamed" phenotype. Methods: This is a new study adding blood leukocyte transcriptomics and bioinformatics analysis to an existing patient cohort of ARDS in patients with sepsis admitted to two ICUs during a 1.5-year period. Canonical pathway analysis was performed. Measurements and Main Results: A total of 210 patients with sepsis and ARDS were included, of whom 128 had a reactive and 82 an uninflamed phenotype. A total of 3,332/11,443 (29%) transcripts were significantly different between the phenotypes. Canonical pathway analysis showed upregulation of oxidative phosphorylation genes indicative of mitochondrial dysfunction (52% of genes in pathway). The uninflamed phenotype was characterized by upregulation of mitogen-activated protein kinase pathways. Conclusions: A third of genes are differentially expressed between biologic phenotypes of ARDS supporting the observation that the subgroups of ARDS are incomparable in terms of pathophysiology. These data provide additional support for biologic heterogeneity in patients with ARDS and suggests that a personalized approach to intervention focusing on oxidative phosphorylation is pivotal in this condition.
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Affiliation(s)
- Lieuwe D J Bos
- 1 Intensive Care, Laboratory of Experimental Intensive Care and Anesthesiology.,2 Department of Respiratory Medicine
| | - Brendon P Scicluna
- 3 Center of Experimental Molecular Medicine, and.,4 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Infection and Immunity, Amsterdam University Medical Center, location Academic Medical Center, Amsterdam, the Netherlands
| | - David S Y Ong
- 5 Department of Microbiology, Julius Center for Health Sciences and Primary Care.,6 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, and
| | - Olaf Cremer
- 7 Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands; and
| | | | - Marcus J Schultz
- 1 Intensive Care, Laboratory of Experimental Intensive Care and Anesthesiology.,8 Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
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Park BH, Shin MH, Douglas IS, Chung KS, Song JH, Kim SY, Kim EY, Jung JY, Kang YA, Chang J, Kim YS, Park MS. Erythropoietin-Producing Hepatoma Receptor Tyrosine Kinase A2 Modulation Associates with Protective Effect of Prone Position in Ventilator-induced Lung Injury. Am J Respir Cell Mol Biol 2019; 58:519-529. [PMID: 29216437 DOI: 10.1165/rcmb.2017-0143oc] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The erythropoietin-producing hepatoma (Eph) receptor tyrosine kinase A2 (EphA2) and its ligand, ephrinA1, play a pivotal role in inflammation and tissue injury by modulating the epithelial and endothelial barrier integrity. Therefore, EphA2 receptor may be a potential therapeutic target for modulating ventilator-induced lung injury (VILI). To support this hypothesis, here, we analyzed EphA2/ephrinA1 signaling in the process of VILI and determined the role of EphA2/ephrinA1 signaling in the protective mechanism of prone positioning in a VILI model. Wild-type mice were ventilated with high (24 ml/kg; positive end-expiratory pressure, 0 cm; 5 h) tidal volume in a supine or prone position. Anti-EphA2 receptor antibody or IgG was administered to the supine position group. Injury was assessed by analyzing the BAL fluid, lung injury scoring, and transmission electron microscopy. Lung lysates were evaluated using cytokine/chemokine ELISA and Western blotting of EphA2, ephrinA1, PI3Kγ, Akt, NF-κB, and P70S6 kinase. EphA2/ephrinA1 expression was higher in the supine high tidal volume group than in the control group, but it did not increase upon prone positioning or anti-EphA2 receptor antibody treatment. EphA2 antagonism reduced the extent of VILI and downregulated the expression of PI3Kγ, Akt, NF-κB, and P70S6 kinase. These findings demonstrate that EphA2/ephrinA1 signaling is involved in the molecular mechanism of VILI and that modulation of EphA2/ehprinA1 signaling by prone position or EphA2 antagonism may be associated with the lung-protective effect. Our data provide evidence for EphA2/ehprinA1 as a promising therapeutic target for modulating VILI.
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Affiliation(s)
- Byung Hoon Park
- 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeonggi Provincial Medical Center Paju Hospital, Paju City, Gyeonggi-Do, Republic of Korea
| | - Mi Hwa Shin
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Ivor S Douglas
- 3 Division of Pulmonary Sciences and Critical Care Medicine, Denver Health Medical Center, University of Colorado School of Medicine, Denver, Colorado
| | - Kyung Soo Chung
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Joo Han Song
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Song Yee Kim
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Eun Young Kim
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Ji Ye Jung
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Young Ae Kang
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Joon Chang
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Young Sam Kim
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
| | - Moo Suk Park
- 2 Division of Pulmonology, The Institute of Chest Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; and
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Zhang N, Zhang Y, Wang L, Xia J, Liang S, Wang Y, Wang Z, Huang X, Li M, Zeng H, Zhan Q. Expression profiling analysis of long noncoding RNAs in a mouse model of ventilator-induced lung injury indicating potential roles in inflammation. J Cell Biochem 2019; 120:11660-11679. [PMID: 30784114 PMCID: PMC7983175 DOI: 10.1002/jcb.28446] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/01/2018] [Accepted: 12/06/2018] [Indexed: 01/24/2023]
Abstract
The key regulators of inflammation underlying ventilator-induced lung injury (VILI) remain poorly defined. Long noncoding RNAs (lncRNAs) have been implicated in the inflammatory response of many diseases; however, their roles in VILI remain unclear. We, therefore, performed transcriptome profiling of lncRNA and messenger RNA (mRNA) using RNA sequencing in lungs collected from mice model of VILI and control groups. Gene expression was analyzed through RNA sequencing and quantitative reverse transctiption polymerase chain reaction. A comprehensive bioinformatics analysis was used to characterize the expression profiles and relevant biological functions and for multiple comparisons among the controls and the injury models at different time points. Finally, lncRNA-mRNA coexpression networks were constructed and dysregulated lncRNAs were analyzed functionally. The mRNA transcript profiling, coexpression network analysis, and functional analysis of altered lncRNAs indicated enrichment in the regulation of immune system/inflammation processes, response to stress, and inflammatory pathways. We identified the lncRNA Gm43181 might be related to lung damage and neutrophil activation via chemokine receptor chemokine (C-X-C) receptor 2. In summary, our study provides an identification of aberrant lncRNA alterations involved in inflammation upon VILI, and lncRNA-mediated regulatory patterns may contribute to VILI inflammation.
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Affiliation(s)
- Nan‐Nan Zhang
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina,Graduate School of Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Yi Zhang
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina
| | - Lu Wang
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina
| | - Jin‐Gen Xia
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina
| | - Shun‐Tao Liang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical UniversityBeijingChina
| | - Yan Wang
- Graduate School of Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Zhi‐Zhi Wang
- Graduate School of Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Xu Huang
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina
| | - Min Li
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina
| | - Hui Zeng
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical UniversityBeijingChina
| | - Qing‐Yuan Zhan
- Center for Respiratory Diseases, China‐Japan Friendship HospitalBeijingChina,Department of Pulmonary and Critical Care MedicineChina‐Japan Friendship HospitalBeijingChina,National Clinical Research Center for Respiratory DiseasesBeijingChina,Graduate School of Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
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Pao HP, Liao WI, Wu SY, Hung KY, Huang KL, Chu SJ. PG490-88, a derivative of triptolide, suppresses ischemia/reperfusion-induced lung damage by maintaining tight junction barriers and targeting multiple signaling pathways. Int Immunopharmacol 2018; 68:17-29. [PMID: 30599444 DOI: 10.1016/j.intimp.2018.12.058] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 12/08/2018] [Accepted: 12/25/2018] [Indexed: 12/27/2022]
Abstract
Previous studies demonstrated that triptolide (PG490) has many anti-inflammatory and immunosuppressive effects. However, little is known about the effect of PG490-88 (a water-soluble derivative of triptolide) on ischemia/reperfusion (I/R)-induced acute lung injury. We assessed the effects of PG490-88 on I/R-induced acute lung injury in rats and on hypoxia/reoxygenation (H/R) in a line of murine epithelial cells. Isolated perfused rat lungs were subjected to 40 min of ischemia, followed by 60 min of reperfusion to induce I/R injury. Induction of I/R led to lung edema, elevated pulmonary arterial pressure, histological evidence of lung inflammation, oxidative stress, and increased levels of TNF-α and CINC-1 in bronchoalveolar lavage fluid. PG490-88 significantly suppressed all of these responses. Additionally, induction of I/R reduced the expression of claudin-4, occludin, and ZO-1, and increased apoptosis in lung tissue. PG490-88 also significantly suppressed these effects. I/R reduced the levels of IκB-α and MKP-1, and increased the levels of nuclear NF-κB and mitogen-activated protein kinase in lung tissue, and PG490-88 suppressed these effects. In vitro studies using mouse lung alveolar epithelial cells indicated that H/R increased the levels of phosphorylated p65 and MIP-2, but decreased the level of IκB-α. PG490-88 also suppressed these effects. In I/R damaged lungs, PG490-88 suppresses the inflammatory response, disruption of tight junction structure, and apoptosis. PG490-88 has the potential as a prophylactic agent to prevent I/R-induced lung injury.
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Affiliation(s)
- Hsin-Ping Pao
- The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Wen-I Liao
- The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Emergency Medicine, Tri-Service General Hospital, Taipei, Taiwan
| | - Shu-Yu Wu
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Kuei-Yi Hung
- The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Kun-Lun Huang
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan.
| | - Shi-Jye Chu
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
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10
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Wang X, Luo B, Lu Y, Pang D, Zheng J, Mo J, Huang H, Feng J. The triggering receptor expressed by myeloid cells-1 activates TLR4-MyD88-NF-κB-dependent signaling to aggravate ventilation-induced lung inflammation and injury in mice. Cell Tissue Res 2018; 374:137-148. [PMID: 29869715 DOI: 10.1007/s00441-018-2853-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 04/17/2018] [Accepted: 05/04/2018] [Indexed: 01/09/2023]
Abstract
The triggering receptor expressed by myeloid cells-1 (TREM-1) plays an important role in infectious and autoimmune diseases but how it contributes to ventilation-induced lung injury (VILI) and inflammation is unclear. Here, we examine the possibility that TREM-1 activates signaling dependent on Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and nuclear factor (NF)-κB, which leads in turn to VILI. In a mouse model of VILI, which we validated based on lung edema and histopathology as well as cytokine levels, we examine mRNA and protein levels of TREM-1, TLR4, MyD88, NF-κB and its inhibitory protein I-κB in animals subjected to ventilation at normal or high tidal volume. The extent of lung edema, injury and inflammation were higher in the high tidal volume animals, as were the expression levels of all proteins examined. Treatment with TREM-1 agonist aggravated these effects, whereas treatment with TREM-1 antagonist attenuated them. Our results suggest that aggravation of VILI by TREM-1 in mice may be associated with TLR4-MyD88-NF-κB-dependent signaling.
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Affiliation(s)
- Xiaoxia Wang
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Bijun Luo
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Yanyan Lu
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Dengge Pang
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Jianqiu Zheng
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Jianlan Mo
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Hui Huang
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China
| | - Jifeng Feng
- Department of Anesthesiology, The Maternal and & Child Health Hospital, The Children's Hospital, The Obstetrics & Gynecology Hospital of Guangxi Zhuang Autonomous Region, Xiang Zhu Rd No. 59, Nanning, 530002, People's Republic of China.
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11
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Sweeney TE, Lofgren S, Khatri P, Rogers AJ. Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury. Am J Respir Cell Mol Biol 2017; 57:184-192. [PMID: 28324666 DOI: 10.1165/rcmb.2016-0395oc] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P < 1E-16). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.
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Affiliation(s)
- Timothy E Sweeney
- 1 Stanford Institute for Immunity, Transplantation and Infection.,2 Biomedical Informatics Research, and
| | - Shane Lofgren
- 1 Stanford Institute for Immunity, Transplantation and Infection.,2 Biomedical Informatics Research, and
| | - Purvesh Khatri
- 1 Stanford Institute for Immunity, Transplantation and Infection.,2 Biomedical Informatics Research, and
| | - Angela J Rogers
- 3 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California
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12
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Guérin C. Prone positioning acute respiratory distress syndrome patients. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:289. [PMID: 28828364 DOI: 10.21037/atm.2017.06.63] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Prone position has been used in acute respiratory distress syndrome (ARDS) patients for more than 40 years in ICU. After having demonstrated its capability to significantly improve oxygenation in a large number of patients, sometimes dramatically, this procedure has been found to prevent ventilator-induced lung injury, the primary concern for the intensivists managing ARDS patients. Over the time, several trials have been done, which regularly improved and refined from each other. At the end, significant improvement in survival has been demonstrated in the most severe ARDS patients, at a threshold of 100-150 mmHg PaO2/FiO2 ratio. The effect of proning on survival cannot be predicted and seems unrelated with both severity of oxygenation impairment and oxygenation response to proning. The rate of complication is declining with the increase in centers expertise. The pressure sores are more frequent in prone and require a special attention. Prone position is a key component of lung protective mechanical ventilation and should be used as a first line therapy in association with low tidal volume and neuromuscular blocking agents in patients with severe ARDS.
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Affiliation(s)
- Claude Guérin
- Medical ICU, Croix Rousse Hospital, Lyon, France.,University of Lyon, Lyon, France.,INSERM 955, Créteil, France
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13
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Abstract
The management of the acute respiratory distress syndrome (ARDS) patient is fundamental to the field of intensive care medicine, and it presents unique challenges owing to the specialized mechanical ventilation techniques that such patients require. ARDS is a highly lethal disease, and there is compelling evidence that mechanical ventilation itself, if applied in an injurious fashion, can be a contributor to ARDS mortality. Therefore, it is imperative for any clinician central to the care of ARDS patients to understand the fundamental framework that underpins the approach to mechanical ventilation in this special scenario. The current review summarizes the major components of the mechanical ventilation strategy as it applies to ARDS.
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Affiliation(s)
- Oleg Epelbaum
- a Division of Pulmonary, Critical Care, and Sleep Medicine , Westchester Medical Center, New York Medical College , Valhalla , NY , USA
| | - Wilbert S Aronow
- b Division of Cardiology , Westchester Medical Center, New York Medical College , Valhalla , NY , USA
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14
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Qian F, Deng J, Wang G, Ye RD, Christman JW. Pivotal Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in Inflammatory Pulmonary Diseases. Curr Protein Pept Sci 2016; 17:332-42. [PMID: 26119506 DOI: 10.2174/1389203716666150629121324] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 06/25/2015] [Accepted: 06/26/2015] [Indexed: 01/11/2023]
Abstract
Mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2) is exclusively regulated by p38 MAPK in vivo. Upon activation of p38 MAPK, MK2 binds with p38 MAPK, leading to phosphorylation of TTP, Hsp27, Akt, and Cdc25 that are involved in regulation of various essential cellular functions. In this review, we discuss current knowledge about molecular mechanisms of MK2 in regulation of TNF-α production, NADPH oxidase activation, neutrophil migration, and DNA-damage-induced cell cycle arrest which are involved in the molecular pathogenesis of acute lung injury, pulmonary fibrosis, and non-small-cell lung cancer. Collectively current and emerging new information indicate that developing MK2 inhibitors and blocking MK2-mediated signal pathways are potential therapeutic strategies for treatment of inflammatory and fibrotic lung diseases and lung cancer.
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Affiliation(s)
- Feng Qian
- Department of Internal Medicine, The Ohio State University, 201 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210, USA.
| | | | | | | | - John W Christman
- Department of Internal Medicine, The Ohio State University, 201 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210, USA.
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15
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Wellman TJ, de Prost N, Tucci M, Winkler T, Baron RM, Filipczak P, Raby B, Chu JH, Harris RS, Musch G, Dos Reis Falcao LF, Capelozzi V, Venegas JG, Vidal Melo MF. Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity. Anesthesiology 2016; 125:992-1004. [PMID: 27611185 PMCID: PMC5096592 DOI: 10.1097/aln.0000000000001334] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification and whether topographically differential gene expression consistent with heterogeneous injury occurs in early ARDS. The authors aimed to determine the temporal relationship between pulmonary metabolic activation and density in a large animal model of early ARDS and to assess gene expression in differentially activated regions. METHODS The authors produced ARDS in sheep with intravenous lipopolysaccharide (10 ng ⋅ kg ⋅ h) and mechanical ventilation for 20 h. Using positron emission tomography, the authors assessed regional cellular metabolic activation with 2-deoxy-2-[(18)F]fluoro-D-glucose, perfusion and ventilation with NN-saline, and aeration using transmission scans. Species-specific microarray technology was used to assess regional gene expression. RESULTS Metabolic activation preceded detectable increases in lung density (as required for clinical diagnosis) and correlated with subsequent histologic injury, suggesting its predictive value for severity of disease progression. Local time courses of metabolic activation varied, with highly perfused and less aerated dependent lung regions activated earlier than nondependent regions. These regions of distinct metabolic trajectories demonstrated differential gene expression for known and potential novel candidates for ARDS pathogenesis. CONCLUSIONS Heterogeneous lung metabolic activation precedes increases in lung density in the development of ARDS due to endotoxemia and mechanical ventilation. Local differential gene expression occurs in these early stages and reveals molecular pathways relevant to ARDS biology and of potential use as treatment targets.
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Affiliation(s)
- Tyler J Wellman
- From the Departments of Anesthesia, Critical Care and Pain Medicine (T.J.W., M.T., T.W., G.M., L.F.d.R.F., J.G.V., M.F.V.M.) and Medicine (Pulmonary and Critical Care; R.S.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Medical Intensive Care Unit, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France (N.d.P.); Department of Medicine (Pulmonary and Critical Care) (R.M.B., P.F.) and Channing Laboratory (B.R., J.-h.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and Laboratory of Histomorphometry and Lung Genomics, University of Sao Paulo, Sao Paulo, Brazil (V.C.)
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16
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Scholten EL, Beitler JR, Prisk GK, Malhotra A. Treatment of ARDS With Prone Positioning. Chest 2016; 151:215-224. [PMID: 27400909 DOI: 10.1016/j.chest.2016.06.032] [Citation(s) in RCA: 241] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/11/2016] [Accepted: 06/29/2016] [Indexed: 12/15/2022] Open
Abstract
Prone positioning was first proposed in the 1970s as a method to improve gas exchange in ARDS. Subsequent observations of dramatic improvement in oxygenation with simple patient rotation motivated the next several decades of research. This work elucidated the physiological mechanisms underlying changes in gas exchange and respiratory mechanics with prone ventilation. However, translating physiological improvements into a clinical benefit has proved challenging; several contemporary trials showed no major clinical benefits with prone positioning. By optimizing patient selection and treatment protocols, the recent Proning Severe ARDS Patients (PROSEVA) trial demonstrated a significant mortality benefit with prone ventilation. This trial, and subsequent meta-analyses, support the role of prone positioning as an effective therapy to reduce mortality in severe ARDS, particularly when applied early with other lung-protective strategies. This review discusses the physiological principles, clinical evidence, and practical application of prone ventilation in ARDS.
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Affiliation(s)
- Eric L Scholten
- Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, CA.
| | - Jeremy R Beitler
- Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, CA
| | - G Kim Prisk
- Departments of Medicine and Radiology, University of California, San Diego, La Jolla, CA
| | - Atul Malhotra
- Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, CA
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17
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Koulouras V, Papathanakos G, Papathanasiou A, Nakos G. Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review. World J Crit Care Med 2016; 5:121-36. [PMID: 27152255 PMCID: PMC4848155 DOI: 10.5492/wjccm.v5.i2.121] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 01/11/2016] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the "sponge lung" - and the "shape matching" -model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients' response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort.
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18
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Guérin C, Mancebo J. Prone positioning and neuromuscular blocking agents are part of standard care in severe ARDS patients: yes. Intensive Care Med 2015; 41:2195-7. [PMID: 26399890 DOI: 10.1007/s00134-015-3918-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Claude Guérin
- Réanimation Médicale, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Université de Lyon, Lyon, France.,INSERM 955 Eq13, Créteil, France
| | - Jordi Mancebo
- Servei de Medicina Intensiva, Hospital de Sant Pau, C. St Quintí 89, 08041, Barcelona, Spain.
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19
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Woods SJ, Waite AAC, O'Dea KP, Halford P, Takata M, Wilson MR. Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 2015; 308:L912-21. [PMID: 25770178 PMCID: PMC4421782 DOI: 10.1152/ajplung.00048.2015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/07/2015] [Indexed: 02/07/2023] Open
Abstract
Mechanical ventilation, through overdistension of the lung, induces substantial inflammation that is thought to increase mortality among critically ill patients. The mechanotransduction processes involved in converting lung distension into inflammation during this ventilator-induced lung injury (VILI) remain unclear, although many cell types have been shown to be involved in its pathogenesis. This study aimed to identify the profile of in vivo lung cellular activation that occurs during the initiation of VILI. This was achieved using a flow cytometry-based method to quantify the phosphorylation of several markers (p38, ERK1/2, MAPK-activated protein kinase 2, and NF-κB) of inflammatory pathway activation within individual cell types. Anesthetized C57BL/6 mice were ventilated with low (7 ml/kg), intermediate (30 ml/kg), or high (40 ml/kg) tidal volumes for 1, 5, or 15 min followed by immediate fixing and processing of the lungs. Surprisingly, the pulmonary endothelium was the cell type most responsive to in vivo high-tidal-volume ventilation, demonstrating activation within just 1 min, followed by the alveolar epithelium. Alveolar macrophages were the slowest to respond, although they still demonstrated activation within 5 min. This order of activation was specific to VILI, since intratracheal lipopolysaccharide induced a very different pattern. These results suggest that alveolar macrophages may become activated via a secondary mechanism that occurs subsequent to activation of the parenchyma and that the lung cellular activation mechanism may be different between VILI and lipopolysaccharide. Our data also demonstrate that even very short periods of high stretch can promote inflammatory activation, and, importantly, this injury may be immediately manifested within the pulmonary vasculature.
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Affiliation(s)
- Samantha J. Woods
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Alicia A. C. Waite
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Kieran P. O'Dea
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Paul Halford
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Masao Takata
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Michael R. Wilson
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
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20
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Ying H, Kang Y, Zhang H, Zhao D, Xia J, Lu Z, Wang H, Xu F, Shi L. MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 194:1239-1251. [PMID: 25520401 DOI: 10.4049/jimmunol.1402088] [Citation(s) in RCA: 162] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127-mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti-miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases.
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Affiliation(s)
- Hangjie Ying
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China
| | - Yanhua Kang
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China
| | - Hang Zhang
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China
| | - Dongjiu Zhao
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China
| | - Jingyan Xia
- Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; and
| | - Zhe Lu
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China
| | - Huanhuan Wang
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China
| | - Feng Xu
- Department of Infectious Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Liyun Shi
- Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China;
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21
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Müller-Redetzky HC, Lienau J, Witzenrath M. The Lung Endothelial Barrier in Acute Inflammation. THE VERTEBRATE BLOOD-GAS BARRIER IN HEALTH AND DISEASE 2015. [PMCID: PMC7123850 DOI: 10.1007/978-3-319-18392-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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22
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Guerin C, Baboi L, Richard JC. Mechanisms of the effects of prone positioning in acute respiratory distress syndrome. Intensive Care Med 2014; 40:1634-42. [PMID: 25266133 DOI: 10.1007/s00134-014-3500-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 09/17/2014] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Prone positioning has been used for many years in patients with acute respiratory distress syndrome (ARDS). The initial reason for prone positioning in ARDS patients was improvement in oxygenation. It was later shown that mechanical ventilation in the prone position can be less injurious to the lung and hence the primary reason to use prone positioning is prevention of ventilator-induced lung injury (VILI). MATERIAL AND METHODS A large body of physiologic benefits of prone positioning in ARDS patients accumulated but these failed to translate into clinical benefits. More recently, meta-analyses and randomized controlled trial in a specific subgroup of ARDS patients demonstrated that prone positioning can improve survival. This review covers the effects of prone positioning on oxygenation, respiratory mechanics, and VILI. CONCLUSIONS We conclude with the effects of prone positioning on patient outcome, in particular on survival.
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Affiliation(s)
- C Guerin
- Service de Réanimation Médicale, Hôpital de la croix-rousse, CHU de Lyon, Bâtiment R, 2ème étage, 103 Grande rue de la croix-rousse, 69004, Lyon, France,
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23
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Otulakowski G, Engelberts D, Gusarova GA, Bhattacharya J, Post M, Kavanagh BP. Hypercapnia attenuates ventilator-induced lung injury via a disintegrin and metalloprotease-17. J Physiol 2014; 592:4507-21. [PMID: 25085885 DOI: 10.1113/jphysiol.2014.277616] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Hypercapnic acidosis, common in mechanically ventilated patients, has been reported to exert both beneficial and harmful effects in models of lung injury. Understanding its effects at the molecular level may provide insight into mechanisms of injury and protection. The aim of this study was to establish the effects of hypercapnic acidosis on mitogen‐activated protein kinase (MAPK) activation, and determine the relevant signalling pathways. p44/42 MAPK activation in a murine model of ventilator‐induced lung injury (VILI) correlated with injury and was reduced in hypercapnia. When cultured rat alveolar epithelial cells were subjected to cyclic stretch, activation of p44/42 MAPK was dependent on epidermal growth factor receptor (EGFR) activity and on shedding of EGFR ligands; exposure to 12% CO2 without additional buffering blocked ligand shedding, as well as EGFR and p44/42 MAPK activation. The EGFR ligands are known substrates of the matrix metalloprotease ADAM17, suggesting stretch activates and hypercapnic acidosis blocks stretch‐mediated activation of ADAM17. This was corroborated in the isolated perfused mouse lung, where elevated CO2 also inhibited stretch‐activated shedding of the ADAM17 substrate TNFR1 from airway epithelial cells. Finally, in vivo confirmation was obtained in a two‐hit murine model of VILI where pharmacological inhibition of ADAM17 reduced both injury and p44/42 MAPK activation. Thus, ADAM17 is an important proximal mediator of VILI; its inhibition is one mechanism of hypercapnic protection and may be a target for clinical therapy.
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Affiliation(s)
- Gail Otulakowski
- Physiology and Experimental Medicine Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Canada
| | - Doreen Engelberts
- Physiology and Experimental Medicine Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Canada
| | - Galina A Gusarova
- Departments of Medicine and Physiology, Columbia University, New York, NY, USA
| | - Jahar Bhattacharya
- Departments of Medicine and Physiology, Columbia University, New York, NY, USA
| | - Martin Post
- Physiology and Experimental Medicine Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Canada
| | - Brian P Kavanagh
- Physiology and Experimental Medicine Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Canada Departments of Critical Care Medicine and Anaesthesia, Hospital for Sick Children, University of Toronto, Toronto, Canada
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24
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5-Lipoxygenase activating protein (FLAP) dependent leukotriene biosynthesis inhibition (MK591) attenuates Lipid A endotoxin-induced inflammation. PLoS One 2014; 9:e102622. [PMID: 25025775 PMCID: PMC4099325 DOI: 10.1371/journal.pone.0102622] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 06/20/2014] [Indexed: 01/08/2023] Open
Abstract
The Lipid A moiety of endotoxin potently activates TLR-4 dependent host innate immune responses. We demonstrate that Lipid-A mediated leukotriene biosynthesis regulates pathogen-associated molecular patterns (PAMP)-dependent macrophage activation. Stimulation of murine macrophages (RAW264.7) with E. coli 0111:B4 endotoxin (LPS) or Kdo2-lipid A (Lipid A) induced inflammation and Lipid A was sufficient to induce TLR-4 mediated macrophage inflammation and rapid ERK activation. The contribution of leukotriene biosynthesis was evaluated with a 5-lipoxygenase activating protein (FLAP) inhibitor, MK591. MK591 pre-treatment not only enhanced but also sustained ERK activation for up to 4 hours after LPS and Lipid A stimulation while inhibiting cell proliferation and enhancing cellular apoptosis. Leukotriene biosynthesis inhibition attenuated inflammation induced by either whole LPS or the Lipid A fraction. These responses were regulated by inhibition of the key biosynthesis enzymes for the proinflammatory eicosanoids, 5-lipoxygenase (5-LO), and cyclooxygenase-2 (COX-2) quantified by immunoblotting. Inhibition of leukotriene biosynthesis differentially regulated TLR-2 and TLR-4 cell surface expression assessed by flow cytometry, suggesting a close mechanistic association between TLR expression and 5-LO associated eicosanoid activity in activated macrophages. Furthermore, MK591 pre-treatment enhanced ERK activation and inhibited cell proliferation after LPS or Lipid A stimulation. These effects were regulated in part by increased apoptosis and modulation of cell surface TLR expression. Together, these data clarify the mechanistic association between 5-lipoxygenase activating protein-mediated leukotriene biosynthesis and 5-LO dependent eicosanoid metabolites in mediating the TLR-dependent inflammatory response after endotoxin exposure typical of bacterial sepsis.
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Kim HJ, Ravichandran K, Ozkok A, Wang Q, He Z, Jani A, Ljubanovic D, Douglas IS, Edelstein CL. The water-soluble triptolide derivative PG490-88 protects against cisplatin-induced acute kidney injury. J Pharmacol Exp Ther 2014; 349:518-25. [PMID: 24727856 DOI: 10.1124/jpet.114.213769] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Triptolide, a traditional Chinese medicine, has anti-inflammatory, antiproliferative, and proapoptotic properties. As interstitial inflammation and tubular apoptosis are features of cisplatin-induced acute kidney injury (AKI), we determined the effect of the water-soluble triptolide derivative 14-succinyl triptolide sodium salt (PG490-88) in a mouse model of cisplatin-induced AKI. PG490-88 resulted in a significant decrease in blood urea nitrogen (BUN), serum creatinine, and acute tubular necrosis (ATN) score, and a nonsignificant increase in tubular apoptosis score in AKI. The mitogen-activated protein kinase (MAPK) pathway is activated in AKI. On immunoblot analysis, phosphoextracellular signal-regulated kinase (p-ERK) was increased 3.6-fold in AKI and 2.0-fold inhibited by PG490-88. Phospho-c-Jun N-terminal kinase (p-JNK) was increased in AKI. PG490-88 resulted in a nonsignificant decrease in p-JNK. Phospho-p38 was not affected by cisplatin or PG490-88. MAPK phosphatase-1 (MKP-1) that negatively regulates MAPK signaling has not previously been studied in AKI. MKP-1 activity was not affected by cisplatin or PG490-88. Changes in p-ERK, p-JNK, and MKP-1 were confirmed on reverse protein phase analysis. The ERK inhibitor U0126 resulted in lower BUN and serum creatinine, suggesting a mechanistic role of ERK in AKI. The increase in interleukin-1α (IL-1α), IL-1β, IL-6, CXCL1, and IL-33 in the kidney in AKI was unaffected by PG490-88. In summary, PG490-88 protects against AKI and ATN despite no decrease in tubular apoptosis. The protection of PG490-88 against AKI was associated with a decrease in p-ERK and was independent of MKP-1 and proinflammatory cytokines. In conclusion, PG490-88 protects against cisplatin-induced AKI possibly by decreasing p-ERK.
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Affiliation(s)
- Hyun-Jung Kim
- Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.) and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., K.R., A.O., Q.W., Z.H., A.J., C.L.E.); and Pulmonary Division, University of Colorado at Denver, Denver, Colorado (I.S.D.)
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Admixture fine-mapping in African Americans implicates XAF1 as a possible sarcoidosis risk gene. PLoS One 2014; 9:e92646. [PMID: 24663488 PMCID: PMC3963923 DOI: 10.1371/journal.pone.0092646] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 02/25/2014] [Indexed: 12/23/2022] Open
Abstract
Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions—6p24.3–p12.1, 17p13.3–13.1, 2p13.3–q12.1, and 6q23.3–q25.2—in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3–p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10−11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3–13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10−6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.
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Dynamics of pulmonary endothelial barrier function in acute inflammation: mechanisms and therapeutic perspectives. Cell Tissue Res 2014; 355:657-73. [PMID: 24599335 PMCID: PMC7102256 DOI: 10.1007/s00441-014-1821-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 01/16/2014] [Indexed: 12/11/2022]
Abstract
The lungs provide a large inner surface to guarantee respiration. In lung alveoli, a delicate membrane formed by endo- and epithelial cells with their fused basal lamina ensures rapid and effective gas exchange between alveolar and vascular compartments while concurrently forming a robust barrier against inhaled particles and microbes. However, upon infectious or sterile inflammatory stimulation, tightly regulated endothelial barrier leakiness is required for leukocyte transmigration. Further, endothelial barrier disruption may result in uncontrolled extravasation of protein-rich fluids. This brief review summarizes some important mechanisms of pulmonary endothelial barrier regulation and disruption, focusing on the role of specific cell populations, coagulation and complement cascades and mediators including angiopoietins, specific sphingolipids, adrenomedullin and reactive oxygen and nitrogen species for the regulation of pulmonary endothelial barrier function. Further, current therapeutic perspectives against development of lung injury are discussed.
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Gattinoni L, Taccone P, Carlesso E, Marini JJ. Prone position in acute respiratory distress syndrome. Rationale, indications, and limits. Am J Respir Crit Care Med 2014; 188:1286-93. [PMID: 24134414 DOI: 10.1164/rccm.201308-1532ci] [Citation(s) in RCA: 283] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In the prone position, computed tomography scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Animal experiments clearly show that prone positioning delays or prevents ventilation-induced lung injury, likely due in large part to more homogeneously distributed stress and strain. Over the last 15 years, five major trials have been conducted to compare the prone and supine positions in acute respiratory distress syndrome, regarding survival advantage. The sequence of trials enrolled patients who were progressively more hypoxemic; exposure to the prone position was extended from 8 to 17 hours/day, and lung-protective ventilation was more rigorously applied. Single-patient and meta-analyses drawing from the four major trials showed significant survival benefit in patients with PaO2/FiO2 lower than 100. The latest PROSEVA (Proning Severe ARDS Patients) trial confirmed these benefits in a formal randomized study. The bulk of data indicates that in severe acute respiratory distress syndrome, carefully performed prone positioning offers an absolute survival advantage of 10-17%, making this intervention highly recommended in this specific population subset.
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Affiliation(s)
- Luciano Gattinoni
- 1 Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Hess DR, Thompson BT, Slutsky AS. Update in acute respiratory distress syndrome and mechanical ventilation 2012. Am J Respir Crit Care Med 2013; 188:285-92. [PMID: 23905523 DOI: 10.1164/rccm.201304-0786up] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Dean R Hess
- Respiratory Care, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
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Herold S, Gabrielli NM, Vadász I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 2013; 305:L665-81. [PMID: 24039257 DOI: 10.1152/ajplung.00232.2013] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In this review we summarize recent major advances in our understanding on the molecular mechanisms, mediators, and biomarkers of acute lung injury (ALI) and alveolar-capillary barrier dysfunction, highlighting the role of immune cells, inflammatory and noninflammatory signaling events, mechanical noxae, and the affected cellular and molecular entities and functions. Furthermore, we address novel aspects of resolution and repair of ALI, as well as putative candidates for treatment of ALI, including pharmacological and cellular therapeutic means.
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Affiliation(s)
- Susanne Herold
- Dept. of Internal Medicine, Justus Liebig Univ., Universities of Giessen and Marburg Lung Center, Klinikstrasse 33, 35392 Giessen, Germany.
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