Acute Respiratory Distress Syndrome (ARDS), the most severe form of acute lung injury, is a common cause of respiratory failure with an overall mortality rate of nearly 40%;however, there are currently no specific pharmacological therapies. A hallmark of ARDS is increased alveolar barrier permeability and decreased clearance of fluid from the airspaces resulting in pulmonary edema. Although work by our group and others has begun to shed light on the regulation of transcellular epithelial ion transport, much less is known about how paracellular permeability and ion transport are regulated in acute lung injury. New research into the regulation of paracellular permeability and selective transport through tight junctions is of fundamental importance to understanding epithelial function in ARDS. In preliminary studies, we have found that tight junction claudins are differentially expressed in acute lung injury. Differential regulation of the claudin family of proteins may represent a central mechanism by which epithelial cells alter the physical properties of the paracellular pathway to control permeability and ion movement. Our hypothesis is that alveolar epithelial cells control the particular tight junction claudins expressed in response to environmental stimuli. We found a significant increase in claudin 4 expression during acute lung injury. This may represent an adaptive response to limit airspace edema formation and allow higher rates of edema clearance because claudin 4 decreases paracellular permeability to large molecules and favors a paracellular pathway that excludes sodium but allows chloride transport. These properties would promote airspace fluid clearance.
In Aim 1, we will determine the functional contribution of claudin 4 to tight junctions using a peptide inhibitor and RNAi in primary rat and human alveolar epithelial type II cells. We will also determine the mechanisms by which claudin 4 and other tight junction protein expression is regulated.
In Aim 2, we will study the function and regulation of claudin 4 in our mouse model of ventilator-induced lung injury.
In Aim 3, we will for the first time examine expression of several claudins in human lungs rejected for transplantation and, using our perfused human lung model, correlate expression levels with measures of epithelial function ex vivo. These studies will provide a more complete understanding of the mechanisms of alveolar epithelial barrier regulation during lung injury and facilitate the development of new therapeutic strategies for ARDS patients.
|LaFemina, Michael J; Sutherland, Katherine M; Bentley, Trevor et al. (2014) Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol 51:550-8|
|Frank, James A; Matthay, Michael A (2014) TGF-? and lung fluid balance in ARDS. Proc Natl Acad Sci U S A 111:885-6|
|Hirsch, Jan; Chalkley, Robert J; Bentley, Trevor et al. (2014) Double impact of cigarette smoke and mechanical ventilation on the alveolar epithelial type II cell. Crit Care 18:R50|
|Yang, Jibing; Wheeler, Sarah E; Velikoff, Miranda et al. (2013) Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins. Am J Pathol 183:1559-1570|
|Frank, James A (2012) Claudins and alveolar epithelial barrier function in the lung. Ann N Y Acad Sci 1257:175-83|
|Rokkam, Deepti; Lafemina, Michael J; Lee, Jae Woo et al. (2011) Claudin-4 levels are associated with intact alveolar fluid clearance in human lungs. Am J Pathol 179:1081-7|
|LaFemina, Michael J; Rokkam, Deepti; Chandrasena, Anita et al. (2010) Keratinocyte growth factor enhances barrier function without altering claudin expression in primary alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 299:L724-34|
|Wray, Charlie; Mao, Ying; Pan, Jue et al. (2009) Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury. Am J Physiol Lung Cell Mol Physiol 297:L219-27|
|Wolters, Paul J; Wray, Charlie; Sutherland, Rachel E et al. (2009) Neutrophil-derived IL-6 limits alveolar barrier disruption in experimental ventilator-induced lung injury. J Immunol 182:8056-62|
|Briot, Raphael; Frank, James A; Uchida, Tokujiro et al. (2009) Elevated levels of the receptor for advanced glycation end products, a marker of alveolar epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human lungs. Chest 135:269-275|
Showing the most recent 10 out of 18 publications