Chronic Alcohol Significantly Affects Pulmonary Function Both at Baseline and in Response to Endotoxemia

Abstract

Acute respiratory distress syndrome (ARDS) is an inflammatory disease characterized by significant pulmonary edema and pathologic alveolar flooding due to disrupted fluid homeostasis and increased alveolar permeability. ARDS accounts for 10% of global ICU admissions annually and carries a significant mortality risk. Chronic alcohol abuse exacerbates acute lung injury and is an independent risk factor to develop ARDS. Alveolar epithelial permeability is regulated by claudin‐family proteins that are incorporated into structures known as tight junctions. We have found that chronic alcohol negatively impacts alveolar barrier function in vitro by changing claudin expression and integration into tight junctions. Defining the molecular mechanisms responsible for the increased incidence of ARDS seen with chronic alcohol abuse is critical to understand the pathology of ARDS. In this study we used an Evans Blue permeability assay to assess changes in alveolar and vasculature permeability due to alcohol in combination with endotoxin as a ‘second‐hit’ to mimic the effects of pneumonia and sepsis on the lung. We also assessed the effects of alcohol and endotoxemia injury on pulmonary barrier function comparing intraperitoneal (IP) and intratracheal (IT) administration. Consistent with previous reports, we found that in alcohol‐fed mice, the alveolar barrier was impaired by both IP and IT endotoxin, allowing Evans Blue to permeate into the airspaces. However, protein content of airspaces was significantly higher in lungs treated with IT endotoxin as compared with IP which we attribute to a heightened inflammatory response in response to endotoxin. We also assessed whether the alcoholic lung is more susceptible to pulmonary edema due to increased fluid pressure from the interstitium (pulmonary wedge pressure). Alcohol‐fed mice showed increased susceptibility to alveolar leak when subjected to increased fluid pressure as compared with water‐fed controls. To test if alcohol‐induced increases in permeability affect pulmonary function and normal gas exchange, arterial oxygen saturation was measured and we found that there was a statistically significant decrease in blood oxygenation in alcohol‐fed mice at baseline as compared with water‐fed controls (97.3 ± 0.3 (n=4) vs 99.3 ± 1 (n=6)) predisposing them to hypoxia. Additionally, we have previously shown that primary alveolar cells cultured from alcohol‐fed rats continue to demonstrate defects in barrier function even after differentiation. We then performed an alcohol withdrawal experiment in mice and found a persistent effect on permeability even after 6 weeks without dietary alcohol. These results suggest alcohol has long lasting effects on the cellular biology and barrier function of alveolar epithelial cells. Current studies are focusing on targeting the tight junction protein Claudin‐5 as a potential mediator of alcoholic lung syndrome, using a specific antagonist peptide to rescue alcohol‐induced barrier dysfunction in vivo.Support or Funding InformationThis work was supported by R01‐AA025854, R01‐HL137112 (M.K.) and K12‐GM000680 (P.S.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.