Acute Respiratory Distress Syndrome (ARDS) is characterized by compromised epithelial function in the terminal alveolus leading to airspace flooding, respiratory failure, and increased mortality. While much has been learned about the pathophysiology of ARDS in the past four decades, the mortality rate remains unacceptably high at ~50%. Surviving ARDS correlates with the ability to maintain lung fluid clearance which, in turn, requires a healthy air-liquid barrier in the lung. This barrier is maintained in large part b alveolar epithelial tight junctions, structures at cell-cell contact sites which form a selectively permeable seal to regulate paracellular diffusion of water, ions and solutes. My laboratory has identified specific roles for proteins known as claudins in regulating alveolar epithelial tight junction permeability. However, the downstream effects of claudin dysregulation in response to acute lung injury (ALI) and ARDS have not been fully elucidated. In addition, chronic alcohol abuse worsens the incidence and severity of ARDS. We have found that chronic dietary alcohol ingestion alters alveolar epithelial claudin expression which correlates with impaired barrier function. Here, molecular tools developed by my laboratory combined with cultured cell and model injury systems will be used to understand how claudin dysregulation affects the progression of ARDS in response to ALI. The project will define mechanistic roles for alveolar epithelial claudins, including claudin-4 and claudin-18 which correlate with improved lung fluid clearance and claudin-5 which is upregulated in the alcoholic lung and associates with impaired alveolar barrier function. A series of adenovectors were developed which allows manipulation of claudin expression by cultured primary alveolar epithelial cells and lung epithelia in vivo. This approach will be used to measure the effects of increasing claudin-4, claudin-5 or claudin-18 expression on alveolar epithelial barrier function. The effects of increasing claudin-4, claudin-5 or claudin-18 on lung fluid clearance in vivo will be assessed and correlated changes to tight junction composition during ALI due to two distinct model systems: 1) intratracheal administration of bleomycin and 2) cecal ligation and puncture to induce sepsis. We will also assess the ability of claudin-4 and claudin-18 to reverse the deleterious effects of alcoholic lung syndrome which exacerbate the pathologic consequences of ALI. Measuring the effects of altered alveolar claudin composition on tight junction permeability and turnover in diverse ALI model systems will be used to evaluate therapeutic strategies with the potential to strengthen alveolar barrier function and lessen susceptibility to ARDS.

Public Health Relevance

Acute lung injury and acute respiratory distress syndrome represent a significant public health problem, with a nearly 40% mortality rate that is further exacerbated in response to chronic alcohol abuse. Patient outcome is significantly connected to the integrity of tight junctions which form the lung air/liquid barrier. The goal of the current research is to understand how lung tight junctions are regulated at a molecular level during sepsis and inflammation in order to identify therapeutic pathways that promote healthy lung function.

National Institute of Health (NIH)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Mitchell, Leslie A; Ward, Christina; Kwon, Mike et al. (2015) Junctional adhesion molecule A promotes epithelial tight junction assembly to augment lung barrier function. Am J Pathol 185:372-86
Capaldo, Christopher T; Farkas, Attila E; Hilgarth, Roland S et al. (2014) Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins. Mol Biol Cell 25:2710-9
Hunt, William R; Zughaier, Susu M; Guentert, Dana E et al. (2014) Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes. Am J Physiol Lung Cell Mol Physiol 306:L43-9
Koval, Michael; Molina, Samuel A; Burt, Janis M (2014) Mix and match: investigating heteromeric and heterotypic gap junction channels in model systems and native tissues. FEBS Lett 588:1193-204