Published online May 14, 2021. doi: 10.3748/wjg.v27.i18.2141
Peer-review started: December 26, 2020
First decision: January 29, 2021
Revised: February 6, 2021
Accepted: March 29, 2021
Article in press: March 29, 2021
Published online: May 14, 2021
Acute lung injury (ALI) is the main reason for the high mortality of patients with severe acute pancreatitis (SAP). Injury and dysfunction of pulmonary microvascular endothelial cells (PMVEC) are considered prerequisites for ALI. The p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway is involved in the development of SAP-related ALI. However, the precise mechanism by which p38 MAPK regulates PMVEC injury in SAP-related ALI is unclear.
To date, no specific pharmacological therapies for SAP associated ALI are available. Elucidating the mechanism of PMVEC injury regulated by p38 MAPK is expected to help identify new treatments for SAP-associated ALI.
To determine the role of p38 MAPK in the tumor necrosis factor-alpha-induced injury of PMVECs in vitro and to explore the effect of SB203580-mediated p38 inhibition on SAP-ALI in vivo.
In vitro, PMVECs were transfected with MAPK kinase 6 (Glu) and stimulated with tumor necrosis factor-alpha to detect cell apoptosis and inflammatory cytokine levels. In vivo, SAP-ALI rats were treated with three different doses of SB203580 (2.5, 5.0 or 10.0 mg/kg). Blood, bronchoalveolar lavage fluid and tissue samples were harvested to assess cytokine levels, blood gas analyses, histopathological changes, myeloperoxidase activity, bronchoalveolar protein concentration, Evans blue extravasa
In vitro, MAPK kinase (Glu) transfection resulted in higher apoptotic rates and cytokine levels in TNF-α-treated PMVECs. In vivo, SB2035080 attenuated lung histopathological injury, decreased inflammatory activity and preserved pulmonary function. Furthermore, SB203580 significantly reversed the microvascular permeability, the increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, the increased expression of apoptosis-related proteins and the endothelial microstructure changes. Moreover, SB203580 significantly reduced pulmonary P-p38, NFκB, P-SATA3 and Myd88 levels but increased the IκB and HO-1 levels.
p38 inhibition may protect against SAP-ALI by alleviating inflammation and the apoptotic death of PMVECs.
In this study, p38 MAPK overactivation promoted PMVEC injury in vitro, while p38 inhibition protected against SAP-ALI in vivo. These results suggest the potential of applying p38 MAPK inhibitors as treatments for SAP-ALI in the clinical setting.