A key role of neurokinin 1 receptors in acute pancreatitis and associated lung injury

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Abstract

Earlier studies have shown that mice deficient in NK1 receptors or its ligand, substance P, are protected against acute pancreatitis and associated lung injury. In the current study, the protective effect of NK1 receptor blockage against acute pancreatitis and associated lung injury was investigated, using a specific receptor antagonist, CP-96345. Acute pancreatitis was induced in mice by intraperitoneal (i.p.) injections of caerulein. Substance P levels in plasma, pancreas, and lungs were found to be elevated in a caerulein dose-dependent manner. Mice treated with CP-96345, either prophylactically, or therapeutically, were protected against acute pancreatitis and associated lung injury as evident by attenuation in plasma amylase, pancreatic and pulmonary myeloperoxidase activities, and histological evidence of pancreatic and pulmonary injuries. Pulmonary microvascular permeability was also reduced as a result of CP-96345 treatment. These results point to a key role of NK1 receptors in acute pancreatitis and associated lung injury.

Section snippets

Materials and methods

Induction of acute pancreatitis. All experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animal (NIH Publication, 1996). Caerulein was obtained from Bachem (Bubendorf, Switzerland). Balb/C mice (20–25 g) were randomly assigned to control or experimental groups using 10 or more animals for each group. Animals were given hourly intraperitoneal (i.p.) injections of normal saline or saline containing caerulein (50 μg kg−1 h−1) for 10 h. CP-96345

Effect of induction of acute pancreatitis on pancreas, lung, and plasma levels of substance P

Hyperstimulation of the pancreas by intraperitoneal administration of caerulein at a dose of 50 μg kg−1 hourly for 3, 6, and 10 h to mice resulted in acute necrotizing pancreatitis as characterized by severe edema, vacuolization, neutrophil infiltration, and acinar necrosis in the pancreas. Moreover, alveolar wall thickening, neutrophil infiltration, and increased cellularity indicated the lung injury associated with this condition. Substance P levels in pancreas, lung, and plasma samples of mice

Discussion

Substance P is a major mediator of neurogenic inflammation, in several tissues, including skin, cardiovascular tissue, cephalic structures, respiratory tract, genitourinary tract, and gastrointestinal tract [6]. NKA has also been shown to play an important role in neurogenic inflammation in several conditions [6]. Indeed, neurogenic inflammation likely underlies several disease conditions, such as asthma, immune-complex-mediated lung injury, experimental arthritis, and inflammatory bowel

Acknowledgments

The authors thank Mei Leng Shoon and Jiali Huang for help with the animal experiments and substance P extraction. The manuscript is supported by Academic Research Fund Grant No. R-184-000-054-112 and Biomedical Research Council Grant No. R-184-000-069-305.

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    These two authors contributed equally to the work.

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