Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury.
BACKGROUND
Tumor necrosis factor alpha (TNF alpha) has been implicated as an important mediator in acute pancreatitis-associated adult respiratory distress syndrome, but the precise pathogenesis remains unclear. The purpose of this work was to clarify the role of TNF alpha that is produced within the lung parenchyma in the inducement of pancreatitis-related pulmonary injury and to examine 1 of the potential pathways leading to the production of pulmonary TNF alpha.


METHODS
Bile salt pancreatitis was induced in rats (n = 40) that were randomized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or vehicle. A separate group (n = 16) underwent sham operation. Pulmonary capillary permeability was determined with fluorescein isothiocyanate-labeled albumin and Evans blue dye, and lung histologic analysis was performed. TNF alpha protein was measured in bronchoalveolar lavage fluid, and p38 MAP kinase was activity determined by Western blot analysis.


RESULTS
The induction of pancreatitis resulted in increased pulmonary capillary leakage and worsened histologic condition (P < .01 vs sham). Effective inhibition of p38 MAP kinase-induced TNF alpha production completely prevented pancreatitis-associated pulmonary injury (P < .01 vs vehicle).


CONCLUSIONS
p38 MAP kinase-induced TNF alpha production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model.
Yang
J
J
Department of Surgery, University of South Florida, Tampa, USA.
Murphy
C
C
Denham
W
W
Botchkina
G
G
Tracey
K J
KJ
Norman
J
J
D000208:Acute Disease; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002199:Capillary Permeability; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D010195:Pancreatitis / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases