Abstract
BackgroundGastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality. Although aspiration-induced local lung inflammation has been studied in animal models, little is known about extrapulmonary effects of aspiration. We investigated whether a single orotracheal instillation of whole gastric fluid elicits a liver acute phase response and if this response contributes to enrich the alveolar spaces with proteins having antiprotease activity.MethodsIn anesthetized Sprague-Dawley rats receiving whole gastric fluid, we studied at different times after instillation (4 h −7 days): changes in blood cytokines and acute phase proteins (fibrinogen and the antiproteases alpha1-antitrypsin and alpha2-macroglobulin) as well as liver mRNA expression of the two antiproteases. The impact of the systemic changes on lung antiprotease defense was evaluated by measuring levels and bioactivity of antiproteases in broncho-alveolar lavage fluid (BALF). Markers of alveolar-capillary barrier derangement were also studied. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used.ResultsSevere peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage and PMNn cell infiltration was seen in the first 24 h and later resolved. Despite a large increase in several lung cytokines, only IL-6 was found elevated in blood, preceding increased liver expression and blood concentration of both antiproteases. These changes, with an acute phase response profile, were significantly larger for alpha2-macroglobulin (40-fold increment in expression with 12-fold elevation in blood protein concentration) than for alpha1-antitrypsin (2–3 fold increment in expression with 0.5-fold elevation in blood protein concentration). Both the increment in capillary-alveolar antiprotease concentration gradient due to increased antiprotease liver synthesis and a timely-associated derangement of the alveolar-capillary barrier induced by aspiration, contributed a 58-fold and a 190-fold increase in BALF alpha1-antitrypsin and alpha2-macroglobulin levels respectively (p < 0.001).ConclusionsGastric contents-induced acute lung injury elicits a liver acute phase response characterized by increased mRNA expression of antiproteases and elevation of blood antiprotease concentrations. Hepatic changes act in concert with derangement of the alveolar capillary barrier to enrich alveolar spaces with antiproteases. These findings may have significant implications decreasing protease burden, limiting injury in this and other models of acute lung injury and likely, in recurrent aspiration.
Highlights
Gastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality
Gastric contents-induced acute lung injury elicits a liver acute phase response characterized by increased mRNA expression of antiproteases and elevation of blood antiprotease concentrations
We found that the severe lung inflammatory reaction induced by orotracheal instillation of whole gastric fluid elicits significant systemic effects that result in upregulation of important lung antiproteases, contributing to improve lung antiprotease defences, underscoring an important role of the liver promoting lung tissue protection in acute lung injury
Summary
Gastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality. The initial local lung effects of aspiration have been extensively studied in animal models [2, 4,5,6,7,8,9,10,11,12,13,14,15]. These effects include severe derangement of the alveolar capillary barrier with extravasation of plasma constituents from the vascular to the alveolar spaces, polymorphonuclear neutrophil recruitment and expression of proinflammatory mediators. We contributed to the understanding of resolution of the initial ALI induced by whole gastric juice in a rat model [5], showing that resolution involves an organizing pneumonia with granuloma formation, that later resolves
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