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Dr. Frank received his medical doctorate degree from the University of Colorado School of Medicine in Denver and went on to residency training in internal medicine at the University of California, San Francisco. He entered the Pulmonary and Critical Care fellowship program at UCSF and the Cardiovascular Research Institute through the ABIM Research Pathway, and pursued research training in Dr. Michael Matthay’s laboratory. Dr. Frank joined the faculty of the Department of Medicine in 2002. Dr. Frank’s primary clinical and research interest is critical care medicine. He is currently an attending physician in the intensive care unit at the San Francisco VA Medical Center.
Research Interests
Acute lung injury, including acute respiratory distress syndrome (ARDS), is a common clinical problem and accounts for 75,000 deaths per year in the U.S. Acute lung injury is characterized by the loss of alveolar barrier function, especially increased alveolar epithelial and vascular endothelial permeability and decreased rates of alveolar edema fluid clearance from the airspaces. Clinical data have demonstrated that preserved alveolar barrier function is associated with lower mortality in patients with acute lung injury and ARDS; however the mechanisms for alveolar barrier regulation are incompletely understood. There are currently no effective pharmacologic therapies for acute lung injury. The overall objective of Dr. Frank’s research program is to understand the regulation of alveolar barrier function so that new treatments for acute lung injury may be developed.
Ongoing Work
A primary focus of the laboratory is to understand the regulation and functional consequences of differential expression of alveolar epithelial tight junction proteins during lung injury and repair. Dr. Frank’s laboratory has found that one way alveolar epithelial cells respond to injury is to change the specific tight junction claudin proteins they express. Claudins are a family of proteins that connect adjacent cells together. The laboratory studies the hypothesis that alveolar epithelial cells change the repertoire of claudins expressed to alter barrier properties. For example, claudin 4 protein expression is markedly up-regulated during lung injury. Inhibition of claudin 4 expression with RNAi or a claudin 4 blocking peptide cloned in Dr. Frank’s laboratory results in more severe pulmonary edema and lung injury. Electrophysiology studies show that claudin 4 confers chloride selectivity to the paracellular pathway, excluding sodium and increasing epithelial fluid transport - an effect that limits pulmonary edema. Therefore, induction of claudin 4 expression represents a protective response to injurious environmental stimuli. Ongoing studies are exploring the mechanisms for the regulation of claudin 4 expression and the function of other alveolar epithelial claudins in cell culture systems, animal models, and perfused human lungs. These studies will provide insight into the mechanisms underlying barrier dysfunction during lung injury, and may also provide broader insight into the role of claudins in tissue repair, development, and cancer. Because alveolar barrier dysfunction is a hallmark of acute lung injury that is associated with mortality in patients, further study into the role of claudins in alveolar epithelial barrier regulation may lead to new therapies for acute lung injury patients.
Selected Publications
Frank JA, Wang Y, Osorio O, Matthay MA. ß-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. J Appl Physiol. 89:1255-1265, 2000.
Frank JA, Gutierrez J, Jones K, Allen L, Dobbs L, Matthay M. Low tidal volume reduces epithelial and endothelial injury in acid-injured rat lungs. Am J Resp Crit Care Med. 165:242-249, 2002.
Frank JA, Pittet JF, Lee, H, Matthay, MA. High tidal volume ventilation induces NOS2 and impairs cAMP-dependent airspace fluid clearance. Am J Physiol, 284: L791-98, 2003.
Frank JA, Matthay, MA. Mechanisms of Ventilator-Induced Lung Injury. Critical Care, 7:233-41, 2003.
Frank J, Roux J, Kawakatsu H, Su G, Dagenais A, Berthiaume Y, Howard M, Canessa C, Fang XH, Sheppard D, Matthay MA, Pittet JF. TGF-ß1 reduces alveolar epithelial sodium and fluid transport via an ERK 1/2-dependent mechanism. J Biol Chem. 2003 Nov 7;278(45):43939-50.
Frank JA, McAuley DF, Fang XH, Matthay MA. Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury. Crit Care Med. 2004 Jul;32(7):1470-6.
Frank JA, McAuley D, Gutierrez J, Daniel B, Dobbs L, Matthay MA. Differential effects of sustained inflation recruitment maneuvers on alveolar epithelial and lung endothelial injury. Crit Care Med. 2005 Jan;33(1):181-8.
Dotson RH, Daniel BM, and Frank JA. General Principles of Managing the Patient with Respiratory Failure in Chest Medicine – Essentials of Pulmonary and Critical Care Medicine. Fifth edition. R.B. George, R.W. Light, M.A. Matthay, R.A. Matthay eds. 2005. Baltimore, Maryland, Williams and Wilkins, pp 517-534.
Frank JA, Matthay MA. Leukotrienes in acute lung injury: A potential therapeutic target. Am J Respir Crit Care Med. 172(3):261-2, 2005.
Godzich M, Hodnett M, Frank J, Su G, Pespeni M, Angel A, Howard M, Matthay M, Pittet JF. Activation of the stress protein response prevents the development of pulmonary edema by inhibiting VEGF cell signaling in a model of lung ischemia-reperfusion injury in rats. The FASEB Journal. 2006;20:1519-152.
Frank JA and Matthay MA. “Ventilator-induced alveolar epithelial injury” in Ventilator-Induced Lung Injury. Dreyfus D, Saumone G, Hubmayr R eds. Vol 215 in the series Lung Biology in Health and Disease. Taylor and Francis, New York, pp377-401, 2006.
Frank JA, Parsons P, Matthay M. Pathogenetic significance of biological markers of ventilator-associated lung injury in experimental and clinical studies. Chest 130:1906-1914, 2006.
Frank J, Wray C, McAuley D, Schwendener R, Matthay, M. Alveolar macrophages contribute to alveolar epithelial barrier dysfunction in ventilator-induced lung injury. Am J Physiol LCMP, 2006; 291:1191-1198.
Su G, Hodnett M, Wu N, Frank JA, Kosinski C, Godzich M, Atakilit A, Matthay M, Sheppard D, and Pittet JF. Integrin αvβ5 regulates pulmonary endothelial permeability and acute lung injury. Am J Respir Cell Mol Biol. 2007; 36(3):377-86.
Hirsch J, Hansen K, Frank JA, Chalkley R, Fang X, Trinidad J, Baker P, Burlingame AL, Matthay M. Impact of low and high tidal volume on the rat alveolar epithelial type II cell proteome. Am J Respir Crit Care Med. 2007; 175(10):1006-13.
Frank JA, Briot R, Lee JW, Ishizaka A, Uchida T, Matthay M. Physiological and biochemical studies of lung fluid balance in human lungs rejected for transplantation. Am J Physiol LCMP 2007 Mar 9. PMID: 17351061
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