research

William Altemeier Charles Frevert Sina Gharib Robb Glenny Gus Matute-Bello
Tom Robertson Erik Swenson
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Integrative Respiratory Physiology Program

The care of patients with critical illness or respiratory diseases requires a sophisticated command of both respiratory and cardiovascular physiology. While powerful molecular biology methods have moved the primary research focus in physiology to cellular and molecular levels, those discoveries invariably raise new questions with respect to how the findings relate to intact organ function. The role for integrative physiology in the molecular biology era is to investigate how new information obtained at the cellular level of function can be applied to the understanding of intact organ systems and whole body responses to a variety of medically relevant stresses. We believe that an integrative approach is needed to investigate the underlying pathways of information and function that originate from a cellular level up through increasingly complex levels of organization. Our respiratory physiology research seeks to integrate genetic, molecular, and cellular biology into the physiology of intact systems.

The modern approach to studying and analyzing systems biology and organ level physiology requires rigorous and advanced techniques in optical imaging, molecular genetics, and computer-assisted analysis of complex interactions. Our integrative respiratory physiology program incorporates these multi-disciplinary and sophisticated approaches towards a more complete understanding of normal physiology and mechanisms underlying disease. Our program focuses on six facets of integrative physiology: 1) physiologic phenotypes of genetically altered mice; 2) translation of molecular and cellular biology discoveries to whole animal physiology; 3) physiologic imaging of interactions between cells and the endothelium of the pulmonary microcirculation; 4) development of computational biology methods to analyze large datasets derived from genomics, transcriptomics and proteomics; 5) mathematical modeling of lung physiology; and 6) pure pulmonary physiology in unique animal models such as lung transplantation in dogs with mixed hematopoietic chimeras.

The various labs and scientists within the Pulmonary and Critical Care Division that constitute the Integrative Respiratory Physiology program are listed below. More information is available by clicking their names.

William Altemeier focuses on transcriptional regulation during lung injury. His focus is on redox sensitive transcription factors and modulation of TLR signaling by mechanical ventilation. He uses multiple murine models combined with state of the art molecular and cellular biology methods to investigate transcriptional regulation in the setting of clinically relevant models of lung injury.

Chuck Frevert focuses on the interaction of chemokines with extracellular matrix and the regulation of cytokine and chemokine production in the lungs. A variety of different methods are used, including techniques to study whole animals, techniques to study intact leukocytes and other cells in vitro, and molecular techniques to study morphological changes in tissue.

Sina Gharib contributes his mathematical modeling and computational skills by applying systems biology analyses to respiratory, sleep and cardiovascular disorders.

Robb Glenny uses comparative animal models to gain insights into determinants of regional pulmonary blood flow and ventilation. He uses novel imaging devices, fractal mathematics and computer modeling in his research.

Gus Matute-Bello is interested in understanding the mechanisms leading to alveolar epithelial damage in acute lung injury, and the interactions of those mechanisms with lung host defenses. He has focused primarily on the role of apoptosis in the development of epithelial damage, with a particular emphasis on the Fas/FasL system. He work combines genomic and proteomic analyses, molecular biology techniques, cell biology, and experimental models of lung injury.

Tom Robertson investigates local mechanisms determining the matching of ventilation and blood flow in the lung, utilizing both gas exchange measurements and high-resolution images of fluorescent markers of ventilation and pulmonary blood flow. A secondary focus is his long-established clinical interest in the physiology of exercise limitation encountered in a wide range disease conditions.

Erik Swenson is an internationally recognized expert in the physiology of carbon dioxide and hypoxia as they relate to gas exchange, ventilation-perfusion matching, control of ventilation and vascular regulation in a variety of situations ranging from humans at high altitude to fish in hypoxic/acidic waters. These studies often involve field studies in stressful environments. His work in lung injury models is focused on therapies that augment endogenous nitric oxide formation and antioxidant defenses. Swenson’s laboratory at the VA Medical Center is recognized for work on carbonic anhydrase in a variety of organ systems and at the integrated whole animal level.

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