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 d istress 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 inj ury and to examine 1 of the potential pathways leading to the production of pulmonary TNF alpha. Methods: Bile salt pancreatitis was indued in mts (n = 40) that were random ized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or v ehicle. A separate group. (n = 16) underwent sham operation. Pulmonary capi llary permeability was determined with fluorescein isothiocyanate-labeled a lbumin and Evans blue dye: and lung histologic analysis runs performed. TNF alpha protein was measured in bronchoalveolar lavage fluid, and p38 MAP ki nase was activity determined by Western blot analysis. Results: The induction of pancreatitis resulted in increased pulmonary capi llary leakage and worsened histologic condition (P < .01 vs sham). Effectiv e inhibition of p38 MAP kinase-induced TNF alpha production completely prev ented pancreatitis-associated pulmonary injury (P < .01 vs vehicle). Conclusions: P38 MAP kinase-induced TNF alpha production plays a central ro le in the development of pulmonary dysfunction, which accompanies severe ac ute pancreatitis in this rodent model.