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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL116958-02
Application #
8706221
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Schlingmann, Barbara; Overgaard, Christian E; Molina, Samuel A et al. (2016) Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions. Nat Commun 7:12276
Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe et al. (2016) Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. Shock :
Liu, Fei; Koval, Michael; Ranganathan, Shoba et al. (2016) Systems Proteomics View of the Endogenous Human Claudin Protein Family. J Proteome Res 15:339-59
Molina, Samuel A; Stauffer, Brandon; Moriarty, Hannah K et al. (2015) Junctional abnormalities in human airway epithelial cells expressing F508del CFTR. Am J Physiol Lung Cell Mol Physiol 309:L475-87
Overgaard, Christian E; Schlingmann, Barbara; Dorsainvil White, StevenClaude et al. (2015) The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function. Am J Physiol Lung Cell Mol Physiol 308:L1212-23
Schlingmann, Barbara; Molina, Samuel A; Koval, Michael (2015) Claudins: Gatekeepers of lung epithelial function. Semin Cell Dev Biol 42:47-57
Farkas, Attila E; Hilgarth, Roland S; Capaldo, Christopher T et al. (2015) HNF4α regulates claudin-7 protein expression during intestinal epithelial differentiation. Am J Pathol 185:2206-18
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
Ward, Christina; Schlingmann, Barbara L; Stecenko, Arlene A et al. (2015) NF-κB inhibitors impair lung epithelial tight junctions in the absence of inflammation. Tissue Barriers 3:e982424
Kopanic, Jennifer L; Schlingmann, Barbara; Koval, Michael et al. (2015) Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75). Biochem J 466:571-85

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