Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome.
BACKGROUND
Select pancreatic enzymes, primarily elastase, precipitate pulmonary injury similar to pancreatitis-associated adult respiratory distress syndrome and stimulate leukocyte cytokine production in vitro via nuclear factor kappa B (NF-kappaB) activation. This study explores the effect of systemic pancreatic enzymes on pulmonary NF-kappaB and inhibitory kappa B (IkappaB) proteins and their role in enzyme-induced pulmonary injury.


METHODS
Mice received pancreatic elastase, amylase, lipase, or trypsin intraperitoneally. Bronchoalveolar lavage IkappaBalpha/IkappaBbeta proteins were measured by immunoblot. Pulmonary NF-kappaB activation, tumor necrosis factor (TNF) gene expression, and neutrophil infiltration (myeloperoxidase) were determined and myeloperoxidase experiments repeated in p55 TNF receptor-deficient (TNF KO) animals. Additional animals received pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB activation, and TNF protein and pulmonary microvascular permeability were measured after elastase administration.


RESULTS
Pancreatic elastase induced pulmonary IkappaBalpha/IkappaBbeta degradation (30 minutes), NF-kappaB activation (60 minutes), and TNF gene expression (60 minutes) with subsequent neutrophilic inflammation (4 hours) and microvascular leakage (24 hours), whereas amylase, lipase, and trypsin did not. Furthermore, lung injury was markedly reduced in TNF KO animals and PDTC significantly attenuated TNF production and pulmonary microvascular leakage.


CONCLUSIONS
Pancreatic elastase induces cytokine-mediated lung injury and this pathway involves the NF-kappaB second messenger system, further supporting elastase as a factor linking pancreatic inflammation to systemic illness during severe acute pancreatitis.
Department of Surgery, University of South Florida, Tampa 33601, USA.
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Jaffray
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Yang
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Carter
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Mendez
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Norman
D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D000975:Antioxidants / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020672:I-kappa B Proteins; D008049:Lipase / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D010196:Pancreatic Elastase / Q000378:metabolism*; D010195:Pancreatitis / Q000150:complications / Q000503:physiopathology*; D009195:Peroxidase / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology*; D013859:Thiocarbamates / Q000494:pharmacology; D014357:Trypsin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015703:Antigens, CD; D000975:Antioxidants; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011759:Pyrrolidines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; D009195:Peroxidase; D008049:Lipase; D000681:Amylases; D010196:Pancreatic Elastase; D014357:Trypsin