The STAT4 and STAT6 pathways in pancreatitis-associated lung injury

The STAT pathways are integral to the inflammatory response and these proteins provide a direct link between the cytokine receptors and cytokine-induced gene transcription. We examined the roles of STAT4 and STAT6 in lung injury after caerulein-induced severe acute pancreatitis. We hypothesized that a modified organ expression of cytokines and chemokines that occurs in transgenic mice may affect the systemic response to severe acute pancreatitis.

Acute pancreatitis [13-hourly intraperitoneal injections of caerulein (50 microg/kg body weight, 0.2 mL) or the same volume of saline] was induced in wild-type (BALB/c) and transgenic (STAT4 or STAT6) mice of the same background, 7 to 8 weeks old. The pancreatic and lung tissues were collected at 1, 6, 12, and 24 h after the completion of caerulein administration. Tissue leukocyte sequestration was assessed by myeloperoxidase (MPO) activity. Standard histological staining hematoxylin and eosin was performed and blindly scored by a pathologist for evidence of lung injury (pulmonary edema, accumulations of neutrophils and mononuclear cells, thickness of alveolar-capillary membrane, perivascular infiltrate, and hemorrhage).

Caerulein-treated wild-type mice exhibited increased lung injury score at 1 through 12 h, as compared to saline controls. As compared to wild-type, STAT6-deficient mice had increased lung injury from 1 to 6 h, with full recovery by 12 h. An opposite pattern was observed in STAT4-deficient mice with mild injury seen at 1 and 6 h, and maximal injury at 12 h. MPO activity was significantly increased at 6 h in caerulein-treated wild-type mice compared to saline-treated controls. Caerulein-treated STAT6 and STAT4 mice had markedly increased MPO activity as compared with their saline controls during the first 6 h. Both caerulein-treated STAT4- and STAT6-deficient mice had significantly increased MPO activity in comparison with wild-type mice with pancreatitis at 6 h.

We found the maximal lung injury after caerulein-induced pancreatitis occurred at different time-points in STAT4 and STAT6-deficient mice. These temporal differences may suggest alternative roles in the systemic inflammatory response associated with pancreatitis.