Acute Lung Injury Center
Director: Janet S. Lee, MD
The Acute Lung Injury Center of Excellence is focused on understanding fundamental mechanisms of lung injury and repair, and integrating findings in basic biology with clinical medicine. The program utilizes advanced tools in molecular, biochemical, and clinical investigations. Our research encompasses multiple disciplines including basic, translational, and clinical sciences and joins faculty with diverse expertise in lung biology, immunology, microbiology, molecular genetics, chemistry, computational biology, infectious diseases, pulmonary and critical care medicine to provide broad opportunities in training, education, and research.
The mission of the ALI/ARDS Center is to synergize basic and translational discoveries that can lead ultimately to novel diagnostics, management and treatments for patients with acute lung injury. The objectives are to:
- Create a central hub for integrating discoveries in basic biology with clinical medicine
- Develop tools to probe the biology of host resilience following acute injury
- Promote research in acute injury across the spectrum of lung diseases
- Establish highly integrative network of investigators to study lung injury and repair at the molecular, cellular, tissue, organismal, and population level
The primary program faculty includes Dr. Janet S. Lee, Dr. Prabir Ray, Dr. Bryan McVerry, Dr. Kong Chen, Dr. Mauricio Rojas, Dr. Chunbin Zou, Dr. Bill Chen, Dr. Jonathan Alder, Dr. Keven Robinson, Dr. Georgios Kitsios, Dr. Faraaz Shah, Dr. Tomeka Suber, Dr. John Evankovich, Dr. Chris O’Donnell, and Dr. Michael Donahoe.
Basic Translational Research
Our laboratory studies the biology of critical illness and host determinants of lung injury. Our research focuses upon effector functions of myeloid cells (mononuclear phagocytes and neutrophils), their roles in the initiation and resolution process of injury in tissue sites such as the lungs, and their potential relevance to human disease. In addition, our laboratory has had a long-standing interest in translational research questions at the intersection of vascular medicine and lung biology, particularly with regards to factors derived from hematopoietic cells such as platelets and red blood cells that can influence the course of lung inflammation. We utilize a repertoire of relevant murine models of injury, molecular genetic approaches, in vitro biochemical assays, and human bio-samples to examine innate host defenses of the lung.
The Ray laboratory is interested in immunoregulatory mechanisms of lung inflammation as they relate to disease inception and resolution. Dr. Ray pioneered the development of inducible cell-specific transgenic mice in the early years of his career which he demonstrated an important role of the growth factor KGF in protection from lung injury. The Ray laboratory is currently focused on immune responses to pulmonary infections and the role of lung myeloid cells resembling myeloid-derived suppressor cells (MDSCs) in resolution of lung inflammation during bacterial pneumonia. Ongoing research in his lab is directed at understanding interactions between cells of the innate immune system and airway epithelial cells during respiratory syncytial virus (RSV) infection using both human samples and animal models, which may lead to new approaches to defend against RSV.
Dr. Chen’s laboratory focuses on identifying and studying molecular pathways that modulate the inflammatory cascade, and mitochondrial function and mitophagy in order to develop novel therapeutics for ARDS and other inflammatory diseases. His laboratory seeks to identify therapeutic targets that regulate these processes within the context of a unifying control mechanism which could provide new opportunities for translation of basic observations to pre-clinical models, and ultimately therapeutics for human diseases.
Dr. O’Donnell’s laboratory focuses on integrative physiology with a long-term interest in the effects of systemic hypoxia, including the metabolic effects and glucose regulation during pneumonia and sepsis. His research is based on mouse models of disease with a specific focus on the use of chronically instrumented and freely behaving animals. Dr. O’Donnell’s work has shown that the route of administration of exogenous glucose in sepsis and pneumonia markedly impacts metabolic function and the development of hyperglycemia. Ongoing work is investigating the anti-inflammatory and metabolic preserving effects of incretin hormones as a mechanism for the beneficial effects of enteral glucose in sepsis and pneumonia.
Dr. Chen’s laboratory focuses on studying memory Th17 responses using mouse models of Klebsiella pneumoniae, P. aeruginosa, and Streptococcus pneumoniae. Using the K. pneumoniae model, Dr. Chen demonstrated that immunization induced memory Th17 cells provide serotype/antibody independent protection against a variety of strains of K. pneumoniae including the recently described multidrug resistant New Delhi metallo-beta-lactamase strain. Enhanced Th17 responses appear responsible for the neutrophilic pathology observed in Cystic Fibrosis as well as patients with other chronic lung inflammations. Dr. Chen also found both IL-17A and IL-17-driven chemokines can be suppressed by epigenetic inhibition in human cells ex vivo as well as mouse models in vivo. Ongoing research is focused on defining the epigenetic regulation of IL-17 downstream chemokines in epithelial cells.
Dr. Zou’s laboratory focuses on the molecular behavior of a group of chromatin modulators in lung injury. Microbial pathogens may take advantage of and hijack these molecules or pathways to cause lung epithelial cell death or reprogram innate and adaptive immunity, thus worsening or accelerating the progression of lung injury. Dr. Zou’s laboratory seeks to to identify potential therapeutic target(s) and develop effective remedies for acute lung injury. His laboratory utilizes state-of-art molecular, cellular, and biochemical approaches, genetic cellular and animal models, and human diseased samples to test our hypothesis.
The Alder lab is focused on understanding how telomeres contribute to human health and disease. Telomeres are DNA/protein caps on the ends of our chromosomes and prevent the ends of chromosomes from triggering a DNA damage response. Telomere defects are the most common identifiable cause of idiopathic pulmonary fibrosis and provides a mechanism for host susceptibility to repeated microinjury to the lungs. The Alder lab is investigating the consequences of telomere dysfunction on the lung epithelium, the steps that link telomere dysfunction with activation of fibroblasts, and the deposition of excess collagen underlying the pathogenesis of fibrosis. We use a variety of approaches to interrogate the consequences of telomere dysfunction and hope to uncover novel strategies for treating lung disease.
Dr. Robinson investigates host defense and host contributions to lung injury. Specifically, we study the roles of innate and adaptive immune cells during acute and chronic respiratory infections. Our research focuses on the IL-1 cytokines and how they modulate innate and adaptive host immunity. We use murine models, in vivo and in vitro assays, and human samples to study host defense and lung injury. We study viral, bacterial, fungal and poly-microbial infections and how an initial infection can predispose to secondary infections.
Dr. Evankovich studies the interaction of host-derived damage and pathogen associated molecular pattern (DAMP and PAMP) molecules with their corresponding cellular receptors in mediating lung injury. He identified the E3 Ligase subunit FBXO10 as a critical regulator of the DAMP sensor Receptor for Advanced Glycation End Products (RAGE). Currently, his work focuses on 1) identifying novel DAMP molecules in Acute Lung Injury that function as innate immune activators and 2) how these molecules interact with various DAMP-sensing receptors during acute lung injury.
Dr. Suber studies the role of the ubiquitin-proteasome pathway in regulating key mediators of acute lung injury and inflammation. Specifically, Dr. Suber identified FBXO17 as an F-box protein subunit that recognizes and mediates glycogen synthase kinase-3b (GSK3β) polyubiquitination and degradation to negatively regulate inflammatory cytokine release and enhance cell proliferation in lung epithelia. Dr. Suber’s current work focuses on the immunomodulatory role of the mitochondrial enzyme Acod1 in acute bacterial pneumonia.
Clinical Translational Research
Dr. Donahoe has a broad range of clinical research interests in the critically ill patient population including the management of chronically critically ill patients, ARDS, and hospital quality improvement. He has additional clinical research interest in clinical trial design and implementation and has been involved in a number of high-profile clinical trials pertaining to the ICU population including the ARDS network FACCT trial, and Human Mesenchymal Stem Cells in the Treatment of Acute Lung Injury.
Dr. McVerry’s research interests have focused on sepsis and ARDS populations and in development of novel interventions for treatment. His research has evolved along three thematic directions: 1) mechanisms contributing to glucose dysregulation and brain dysfunction in sepsis, 2) phenotyping patients with critical illness syndromes, and 2) the role of the microbiome in the evolution of and as a potential therapeutic target in critical illness. Dr. McVerry established the University of Pittsburgh Acute Lung Injury Registry and Biospecimen Repository in 2012. The ALIR registry contains clinical data and longitudinal biospecimens from over 500 individuals with or at risk for ARDS. Dr. McVerry is involved with clinical trials in sepsis and ARDS spanning the continuum from phase 1 to phase 3 on a local scale and as an active member of the NIH Prevention and Early Treatment for Acute Lung Injury (PETAL) Network.
Dr. Kitsios’ research interest is in the longitudinal evolution of human microbial communities in the respiratory and aerodigestive tracts of critically-ill, mechanically ventilated patients to understand the potential impact of dysbiosis on the outcome of critical illness. A current research focus is on the use of emerging culture-independent technologies for the rapid and precise diagnosis of culprit pathogens based on profiling of microbial communities in the lung. With computational biology methods, Dr. Kitsios is working towards the development of an integrative, molecular definition of pneumonia and microbial lung injury. Another research focus is the clinical utility of Fecal Microbiota Transplantation for the eradication of MultiDrug Resistant Organisms that frequently colonize the intestinal communities following ICU stay, in order to prevent future, secondary infections.
The Rojas laboratory focuses on the biology of lung injury and repair, especially in models of pulmonary fibrosis, acute lung injury and radiation. Dr. Rojas’ laboratory has produced pioneering work on the development of pre-clinical models for the use of bone marrow derived-mesenchymal stem cells on acute and chronic injury. His novel area of research is the human ex vivo perfusion program, using human normal lungs and diseased lungs, studying the effect of novel therapies like stem cells, non-coding RNAs, small molecules as pre-clinical models for the implementation of new therapies for lung diseases. This protocol in combination of the collection of tissues samples from explanted lungs, has allowed his laboratory to build a program of organ/tissue collection from normal and diseased lungs.
Dr. Shah’s primary research utilizes a bench-to-beside approach to characterize the effects of early enteral nutrients on inflammatory and metabolic pathways in sepsis. In preclinical studies, Dr. Shah’s research focuses on the stimulation of endogenous intestine-derived incretin hormones to promote euglycemia and attenuate the systemic inflammatory response in catheterized septic mouse models. Dr. Shah is translating these findings to a single center randomized clinical trial entitled the Study of Early Enteral Dextrose in Sepsis testing the effects of an early low-level dextrose infusion as a therapeutic agent in septic patients. Within the acute lung injury population, Dr. Shah is exploring the relationships between glycemic control, inflammation, incretin hormones, and the microbiome.
Dr. Barbash conducts health services research investigating the intersection between health policy and critical care. He uses administrative and electronic health record data, employing a variety of clinical and health services research methods to understand how health policy affects the organizational aspects of critical care that contribute to the delivery of evidence-based care and outcomes for patients with sepsis (a common cause of acute lung injury), acute respiratory failure, and other forms of critical illness in the ICU. He is currently supported by a K08 from the Agency for Healthcare Research and Quality to use electronic health record data to evaluate the impact of the first national sepsis quality measurement program.