Acute Lung Injury
The Acute Lung Injury focus group seeks to identify novel mechanisms of lung injury and repair, and explore how these mechanisms may be exploited to develop new therapeutics for patient treatment. Disruption of the endothelial lining in the pulmonary circulation results in widespread alveolar flooding and the development of life-threatening hypoxemia. Historically, research on acute lung injury has focused on understanding the signaling pathways involved in the disruption of the endothelial-epithelial barrier that leads to alveolar flooding. Recovery from acute lung injury requires repair of the disrupted capillary endothelial-alveolar epithelial barrier in the pulmonary microcirculation to re-establish a proper gas exchange unit. The signaling pathways involved in the repair of endothelial and alveolar epithelial cells are distinct from those that lead to the initial injury, and are likely modulated by the local environment. Despite its importance, little is known about the mechanisms involved in pulmonary barrier restoration, and no current therapeutic interventions aim to promote lung repair in affected patients.
Within the CLB, we have a collaborative group of researchers interested in both aspects of acute lung injury, some investigating those factors that initiate acute lung injury (e.g. signaling pathways involved in the disruption of the endothelial-epithelial barrier), and others focused on the mechanisms that promote pulmonary vascular repair. Members of our research team, and their scientific interests, are listed below. This group employs vertically integrated approaches aimed at dissecting acute lung injury, with expertise ranging from intact animal models and whole lung physiology to cell culture and molecular biology. We hope you join us!
Airways and Airway Smooth Muscle
Several laboratories associated with the CLB investigate diverse aspects of development, cell biology and function of the airways and airway smooth muscle. The faculty members are interested in signaling pathways and molecules that regulate lung development, epithelial fluid transport, smooth muscle contraction, cell migration and cell phenotype. Relevant disease interests include asthma, cystic fibrosis and bronchopulmonary dysplasia. A shared theme of each laboratory is interest in defining cellular and molecular mechanisms of lung pathology that might be exploited in developing novel lung-directed therapies for the diseases of interest. Expertise exists in a variety of experimental approaches including functional assays of airway secretion and fluid transport, airway smooth muscle mechanics, lung morphology and histology, cell migration, gene expression and RNA-induced silencing. The broad-based multidisciplinary nature of airways research adds to the highly interactive nature of the CLB.
Pulmonary Endothelial Cell Biology
The Pulmonary Endothelial Cell Biology focus group examines mechanisms that regulate endothelial cell behavior, with a special emphasis on the heterogeneity in structure and function of pulmonary artery, capillary, and vein endothelium. The pulmonary circulation is the largest circulation in the body; it possesses an enormous surface area, especially within the capillaries. Pulmonary endothelium is of the continuous subtype, although in recent years, research has begun to reveal the diverse nature of these cells along the vascular axis. CLB investigators have contributed significantly to our growing awareness of endothelial cell heterogeneity. Our faculty has examined how pulmonary artery, capillary, and vein endothelial cells uniquely respond to diverse environmental stimuli, including oxygen, carbon dioxide, bicarbonate, various inflammatory mediators, bacteria, viruses and parasites. We have addressed divergent functions of these cell types in regard to barrier properties, growth, migration, apoptosis, and the production of vasoactive substances such as nitric oxide and prostacyclin. We have begun to provide complex molecular maps regarding signals that confer endothelial specificity and, further, site-specific endothelial cell specificity. This is an exciting time in the study of endothelial cell biology. Come be a part of our program as we divulge basic mechanisms of endothelial cell structure and function, examine how these mechanisms are disrupted or dysfunctional in disease states, and exploit our novel discoveries for development of new therapies to combat vascular disease.
Pulmonary Arterial Hypertension
The Pulmonary Arterial Hypertension (PAH) focus group investigates the cellular mechanisms of pulmonary vasoconstriction and vascular wall remodeling with the goal of identifying more effective therapy for the debilitating and deadly disease. The etiology of PAH can be idiopathic or heritable, or it can develop secondarily to other underlying conditions. Regardless of etiology, the pathogenesis of the pulmonary arterial disease involves dysregulation of numerous vasoactive mediators and cellular signaling pathways that cause sustained pulmonary vasoconstriction, perivascular inflammation, medial and adventitial thickening of proximal pulmonary arteries, fibroproliferative occlusion of distal pulmonary arteries, and in situ thrombosis. The resulting increased pulmonary arterial resistance and stiffness overload the right ventricle and ultimately lead to its failure and the death of PAH patients. The current clinical management of PAH is hampered by two major impediments. First, the drugs now used are at best only moderately effective. Second, no biomarkers have been identified to provide tracking of either the development of the arteriopathy and right ventricular failure or the response to treatment. Correcting these limitations is imperative to improve quality of life and survival of PAH patients.
Rho kinase (comprising isoforms 1 and 2) is a hub of numerous signal transduction pathways. Whereas basal Rho kinase activity is involved in regulation of normal cellular function, the multifunctional kinase is hyperactivated in various cardiovascular diseases. There is substantial evidence that hyperactive Rho kinase signaling is a key mediator of several of the processes involved in development and progression of PAH. These include endothelial dysfunction, inflammation, vasoconstriction, cell proliferation and migration, fibrosis, and thrombosis. Thus, the central theme of our translational research program is that hyperactivation of Rho kinases not only plays a key role in the pathogenesis of PAH, but also generates circulating biomarkers of the disease severity. The ultimate goal of our group’s collaborative interaction is to establish new therapeutic strategies to effectively and safely inhibit Rho kinase signaling in the hypertensive pulmonary arteries and failing right ventricle of patients with PAH. We also seek to determine if circulating, Rho kinase-related microparticles and microRNAs (miRNAs) are sensitive biomarkers of the pulmonary arteriopathy and right ventricular dysfunction, and of the clinical response to Rho kinase-inhibitor therapy.
Preclinical work is done in our recently characterized late-stage Sugen5416/Hypoxia/Normoxia-exposed rat that shows unusual hemodynamic and pulmonary arteriopathic fidelity to human PAH (Abe et al., Circulation 121: 2747-2754, 2010). This model of occlusive PAH provides a more exacting test of the potential clinical efficacy of new therapeutic candidates than do the traditional chronically hypoxic and monocrotaline-injected models. Appropriate preclinical findings will be tested in clinical trials in PAH patients receiving conventional therapy in the University of South Alabama Medical Center’s Pulmonary Hypertension Center.
Nano-Scale Respiratory Biology
The Nano-Scale Respiratory Biology focus group examines nano- and molecular-scale interactions that govern cellular responses to the environment. In the last decade we have come to appreciate how seemingly small changes in structural components of pulmonary endothelial and smooth muscle cells markedly impact pulmonary function. Our goal is to understand how such changes ultimately impact our ability to breathe. The projects we pursue are often inspired by observations made in the study of pulmonary disease. For example, P. aeruginosa secretes an enzyme that cleaves a particular sugar in the glycocalyx; ongoing studies are aimed at determining whether this damage to the glycocalyx makes the lung more susceptible to infection. P. aeruginosa also injects exotoxins into epithelial and endothelial cells; exotoxins hijack localized signaling complexes in the host cell, cause changes in cellular structure, and make the lung more susceptible to damage. Compromised endothelial cells release small vesicles that deliver signaling molecules and proteins throughout the vasculature and can trigger system wide inflammatory responses.
Historically it has been difficult to study these processes because the small scale of the events precluded direct measurement. We are active in the development of genetic, biochemical, and imaging approaches to overcome these technical limitations. In particular, we are now able resolve dynamic, inter-molecular events that occur in intracellular and extracellular spaces in vitro and in vivo. Even with technical advances, the mechanisms by which small changes within cells impact pulmonary function remain poorly understood, making this an area of research ripe with potential. Studies conducted by members of this group are inherently multidisciplinary, with biologists, clinicians, chemists, and engineers working in concert. This offers an unique and collaborative training environment for students, faculty, and fellows in multifaceted studies of pulmonary physiology and pathophysiology.