Blockade of p38 map kinase inhibits complement-induced acute lung injury in a murine model.
Features of acute lung injury include neutrophil influx and increased vascular permeability with resultant pulmonary edema. Inhibition of p38 mitogen-activated protein kinase (MAPK) in in vivo models of endotoxin-induced inflammation results in reduction of organ injury as well as symptomatic relief. In this study, mice received an oral dose (100 mg/kg) of the p38 MAPK inhibitor, SB203580, followed by intratracheal instillation of an agent of complement origin, C5a des arg, at a concentration (10 microg) that induced acute lung injury. Neutrophil and protein content of bronchoalveolar lavage fluid as indicators of leukocyte influx and vascular permeability respectively were assessed. Animals that received C5a-instillation had a significant influx of neutrophils into the lungs (49+/-8%) while mice receiving C5a-instillation and prior treatment with SB203580 exhibited diminished influx (16+/-5%). Similarly, pretreatment with oral SB203580 resulted in decreased vascular permeability (241+/-34 microg/ml) than the positive control animals (407+/-135 microg/ml). Activity analysis of total lung p38 MAPK revealed that p38 activity was increased at 4 h after C5a-instillation and that SB203580-treated C5a-instilled mouse lungs had lower p38 activity than did the C5a-instilled control. These data indicate that oral administration of an agent inhibitory for p38 MAPK offers a protective effect in the lungs from both neutrophil influx and protein leak associated with acute lung injury.
Nash
Steven P
SP
School of Medicine, Saint Louis University, St. Louis, MO 63104, USA.
Heuertz
Rita M
RM
D000704:Analysis of Variance; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015937:Complement C5a, des-Arginine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007442:Intubation, Intratracheal; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D015937:Complement C5a, des-Arginine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011506:Proteins; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580