Critical role of p38 mitogen-activated protein kinase signaling in septic lung injury.
OBJECTIVE
Leukocyte-mediated tissue damage is a key feature in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of leukocytes remain elusive. The aim of the present study was to define the role of p38 mitogen-activated protein kinase (MAPK) signaling in septic lung injury.


METHODS
Prospective experimental study.


METHODS
University hospital research unit.


METHODS
Male C57BL/6 mice.


METHODS
Pulmonary edema, bronchoalveolar infiltration of leukocytes, levels of myeloperoxidase, and CXC chemokines were determined 6 and 24 hrs after cecal ligation and puncture (CLP). The specific p38 MAPK inhibitors SB 239063 and SKF 86002 were given immediately before CLP induction. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot.


RESULTS
CLP induced clear-cut pulmonary damage characterized by edema formation, leukocyte infiltration, and increased levels of CXC chemokines in the lung. Moreover, CLP increased phosphorylation and activity of p38 MAPK in the lung, which was markedly inhibited by SB 239063. Interestingly, inhibition of p38 MAPK signaling protected against CLP-induced lung damage and edema. Indeed, both SB 239063 and SKF 86002 decreased CLP-induced leukocyte recruitment in the bronchoalveolar space and formation of CXC chemokines in the lung.


CONCLUSIONS
Our data demonstrate that p38 MAPK signaling constitutes a key role in regulating CXC chemokine production in septic lung injury and that inhibition of p38 MAPK activity abolishes pulmonary infiltration of leukocytes as well as lung edema. These novel findings suggest that targeting the p38 MAPK signaling pathway may pave the way for a new therapeutic strategy against lung injury in polymicrobial sepsis.
Asaduzzaman
Muhammad
M
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Wang
Yusheng
Y
Thorlacius
Henrik
H
D000818:Animals; D019743:Chemokines, CXC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011654:Pulmonary Edema / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D019743:Chemokines, CXC; D048051:p38 Mitogen-Activated Protein Kinases