Background: Gastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality.\nAlthough aspiration-induced local lung inflammation has been studied in animal models, little is known about\nextrapulmonary effects of aspiration. We investigated whether a single orotracheal instillation of whole gastric\nfluid elicits a liver acute phase response and if this response contributes to enrich the alveolar spaces with proteins\nhaving antiprotease activity.\nMethods: In anesthetized Sprague-Dawley rats receiving whole gastric fluid, we studied at different times after\ninstillation (4 h âË?â??7 days): changes in blood cytokines and acute phase proteins (fibrinogen and the antiproteases\nalpha1-antitrypsin and alpha2-macroglobulin) as well as liver mRNA expression of the two antiproteases. The impact of\nthe systemic changes on lung antiprotease defense was evaluated by measuring levels and bioactivity of antiproteases\nin broncho-alveolar lavage fluid (BALF). Markers of alveolar-capillary barrier derangement were also studied.\nNon-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used.\nResults: Severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage and PMNn cell\ninfiltration was seen in the first 24 h and later resolved. Despite a large increase in several lung cytokines, only IL-6 was\nfound elevated in blood, preceding increased liver expression and blood concentration of both antiproteases. These\nchanges, with an acute phase response profile, were significantly larger for alpha2-macroglobulin (40-fold increment in\nexpression with 12-fold elevation in blood protein concentration) than for alpha1-antitrypsin (2ââ?¬â??3 fold increment in\nexpression with 0.5-fold elevation in blood protein concentration). Both the increment in capillary-alveolar antiprotease\nconcentration gradient due to increased antiprotease liver synthesis and a timely-associated derangement of the\nalveolar-capillary barrier induced by aspiration, contributed a 58-fold and a 190-fold increase in BALF alpha1-antitrypsin\nand alpha2-macroglobulin levels respectively (p < 0.001).\nConclusions: Gastric contents-induced acute lung injury elicits a liver acute phase response characterized by increased\nmRNA expression of antiproteases and elevation of blood antiprotease concentrations. Hepatic changes act in concert\nwith derangement of the alveolar capillary barrier to enrich alveolar spaces with antiproteases. These findings may\nhave significant implications decreasing protease burden, limiting injury in this and other models of acute lung injury\nand likely, in recurrent aspiration.
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