The Acute Lung Injury (ALI)/ Adult Respiratory Distress Syndrome (ARDS) Research Program is focused on the investigation of fundamental mechanisms in lung injury and repair. The program utilizes advanced tools in molecular, biochemical, and clinical investigation. Extensive collaborative interactions exist with the Departments of Surgery, Anesthesiology, Pathology, and Environmental Health. The primary program faculty includes Dr. Rama K. Mallampalli, Dr. Janet S. Lee, Dr. Bryan McVerry, Dr. Prabir Ray, Dr. Yutong Zhao, and Dr. Michael Donahoe.
The mission of the ALI/ARDS Center is to synergize basic and translational discoveries that can lead to novel treatments for patients with severe acute lung injury. The ALI Center focuses on:
Dr. Mallampalli serves as Director of the ALI program. His primary area of research interest is in the study of molecular mechanisms for control of bioactive lipid mediators in acute lung injury. He has focused on the major phospholipid of animal membranes and of lung surfactant, phosphatidylcholine (PC). This lipid is tightly controlled, in part, by the rate-regulatory phosphoenzyme cytidylyltransferase (CCT). His work investigates the molecular physiology of how CCT is controlled by post-translational modification via enzyme turnover. In models of inflammatory lung injury, surfactant PC biosynthesis is greatly impaired because CCT activity decreases as a result of post-translational enzyme modification and gene transcriptional repression. He has discovered that CCT is coordinately degraded by calpains and the ubiquitin system in models of pulmonary sepsis. These adverse effects are opposed by the calcium- sensor, calmodulin, that binds and stabilizes CCT during infection. Dr. Mallampalli’s second area of research interest is in the molecular control of ubiquitin E3 ligases and how they might impact lipogenic proteins. His investigates how calcium-regulated effectors control site-specific ubiquitination of target lung proteins (e.g. CCT) that in turn ultimately increase degradation of these substrates through proteasome-independent sorting. Dr. Mallampalli uses gene transfer approaches to express new CCT mutant enzymes in alveolar epithelia that are resistant to proteolysis and phosphorylation events thereby restoring surfactant PC to high levels in alveolar injury.
Figure 1. P. aeruginosa (PA103) triggers calcium (Ca2+) influx in lung epithelia. A. Cartoon illustrates the molecular structure of the cameleon construct for sensitive detection of calcium signals using fluorescent resonance enery transfer (FRET) technology. A-B. Cells were infected with baculovirus encoding cameleon prior to culture in medium replete or deplete with Ca2+, followed by PA103 infection. D. Following PA103 infection, cells were washed, fixed, and immunostained for Golgi 97 to visualize the Golgi complex. E. Cells infected with baculovirus encoding cameleon and PA103 as in (B) were processed for analysis of fluorescent CFP and YFP signals. F. Mice were given baculovirus-cameleon, and infected with PA103 (107 CFU i.t./mouse) prior to fluorescent lung imaging.
Dr. Lee's research interest includes neutrophil-mediated lung inflammation and injury. Specifically, Dr. Lee’s laboratory investigates the role of chemokines, chemokine binding proteins and receptors in facilitating the process of lung inflammation. One primary focus of the laboratory is the Duffy antigen, a high affinity inflammatory chemokine binding protein expressed on red cells and endothelium, and its regulation of neutrophilic lung injury and inflammation. The laboratory is currently investigating the role of red cell transfusion in perpetuating thrombo-inflammatory injury in the susceptible host. Dr. Lee’s interest also includes how we examine systemic markers of inflammation in neutrophilic lung diseases such as acute lung injury and chronic obstructive pulmonary disease.
Red cell transfusion in Acute Lung Injury. Under normal conditions, the alveolar epithelium and endothelium provide a tight barrier function preventing the leakage of fluid, protein, and cells into the airspaces. Red cell transfusion may contribute to lung injury by amplifying innate immune activation signals in susceptible hosts to augment neutrophilic inflammation and promote injury. Stored red cells in transfusates may activate endothelium, provide chemokine signals, and microparticles with exposed phosphatidylserine on their surface that may facilitate hemostatic activation.
Dr. McVerry's research interest has focused on the regional pathophysiology of acute lung injury and on pulmonary endothelial function in the acutely injured lung as it pertains to alveolar capillary barrier regulation and the control of pulmonary vascular tone.
Depicted are chest radiographs and corresponding CT scans of three patients with severe ARDS. Note the presence of diffuse airspace opacities on chest radiographs and the regionally heterogenous distribution of lung edema on CT images. Patients were all ventilated with low tidal volume ARDS Network protocol ventilation and all required alternative modes of ventilation and/or adjunctive therapies including prone positioning, inhaled nitric oxide, and/or neuromuscular blockade. All three patients survived to hospital discharge.
Dr. Ray's research program is focused in the following areas:
-Mechanism(s) of keratinocyte growth factor (KGF)-mediated protection of lung from oxidative injury. KGF plays an important role in the repair of lung alveolar epithelium after injury. Using an inducible transgenic approach and molecular biology techniques his group has identified signaling proteins involved in KGF receptor signaling. Currently he is studying signal transduction pathways involving these molecules and their role in the healing process after oxidative injury to the lung.
-Proteomic analysis of lung diseases. Hypothetically, almost all diseases are the result of imbalance in protein expression. Conceptually, a decrease in "good" protein levels and an increase in "bad" protein levels results in disease. Dr. Ray has initiated a project to establish a quantitative differential protein expression profile (proteome) of specific cell types isolated from normal lung and diseased lung and also from BAL. After identification of specific profiles and using molecular biology techniques, he will have a better understanding of disease processes. This will also help to develop differential diagnostic antibody chips for lung diseases.
-Role of dendritic cells in lung inflammation. The dendritic cell (DC) is an important cell in the immune system. It exerts its effects by diverse biochemical processes from antigen processing and presentation to cell migration by producing chemokines. Dr. Ray initiated studies on regulation of chemokine production by DC in Th1- and Th2 driven lung diseases
Dr. Ray is a project leader on the Host Defense SCCOR.
Dr. Zhao’s research focuses on investigating the molecular and cellular factors that preserve integrity of the alveolar-endothelial barrier in acute lung injury. He focuses on the role of lysophosphatidic acid (LPA) and LPA receptors in epithelial barrier function and inflammation. He has previously shown that LPA induces both pro- and anti-inflammatory mediators, such as IL-8, PGE2, and IL-13Ra2. Recent studies from Dr. Zhao’s lab showed that LPA enhances airway epithelial barrier function by regulating E-cadherin / c-Met complex intracellular trafficking. Dr. Zhao uses LPA receptor knockout mice to study the role of LPA and LPA receptors in murine models of LPS-induced acute lung injury and OVA-induced asthma.
Dr. Michael Donahoe is the Medical Director of the MICU and actively directing a broad range of projects focused on patient safety and care quality management in the ICU. He has conducted a broad range of clinical trials in ARDS, nutrition support, catheter management, and nosocomial infections. Collaborations exist with the Department of Critical Care Medicine and the School of Nursing.