Section of Pulmonary / Critical Care Medicine

Section of Pulmonary/Critical Care Basic Research Faculty and Their Interests:

Evgeny V. Berdyshev, Ph.D.

Dr. Berdyshev’s scientific interests are focused on biologically active lipids. His early work was dedicated to marine organisms as a source of biologically active ether lipids and to the synthesis of platelet activating factor (PAF). Significant efforts were made to create cryopreservation media particularly for genetic materials of marine organisms. Following this, his research concentrated on endocannabinoids as immunomodulatory and signaling molecules. This research led to a demonstration of signaling potency of endocannabinoid congeners that cannot bind to and activate cannabinoid receptors. A direct link between PAF stimulation and immediate synthesis and release of endocannabinoid 2-arachidonoylglycerol was also discovered. My recent work on sphingolipids and lysophosphatidic acid as mediators of pulmonary inflammation further extends my interest in lipids as active players of inflammatory processes. The development of new mass spectrometric methods for lipid identification and quantitation is one of my actual priorities. The role for lysophospholipids and sphingolipids in lung cancer development is the most interesting direction for the expansion of my research interests.

Steven Dudek, M.D.

Dr. Dudek’s research seeks to mechanistically characterize the regulation of pulmonary vascular barrier function, with a particular emphasis on in vitro and animal models of acute lung injury syndromes. His recent work has focused on endothelial cell (EC) cytoskeletal rearrangements involved in regulating pulmonary vascular leak as well as identifying novel agents for reversing this pathophysiological process. For example, Dr. Dudek has rigorously explored in vitro the structure and function of cortactin, a key actin binding protein linked to dynamic cytoskeletal rearrangement, while focusing on its role in EC barrier function. This work has characterized the functional importance of cortactin interaction with EC myosin light chain kinase, a critical enzyme that generates cell tension through actomyosin interaction, describing novel mechanistic roles for these 2 proteins in reducing pulmonary vascular permeability. More recently, Dr. Dudek’s research has helped characterize the potent barrier enhancing effects of various sphingolipid and related compounds in reversing pulmonary vascular leak models, a therapeutic goal for treating patients with acute lung injury syndromes.

Nickolai Dulin, Ph.D.

Dr. Dulin’s laboratory focuses on the mechanisms of signal transduction mediated by heterotrimeric G proteins in smooth muscle cells (SMC). Numerous vasoactive ligands, such as endothelin-1, angiotensin II, thrombin, ATP, etc., bind G protein coupled receptors (GPCR) at the surface of the cells and stimulate diverse signaling cascades leading to SMC contraction, proliferation, migration and cytokine production. These processes are implicated in the pathogenesis of atherosclerosis, angioplasty-induced restenosis, pulmonary hypertension and asthma. Using cellular and molecular biology approaches, he is trying to identify the common signaling molecules implicated in SMC pathophysiology and to find the way of their regulation. These include various G proteins and their regulators (RGS proteins), protein kinases and transcription factors.

Konstantin Birukov, M.D., Ph.D.

Dr. Birukov’s laboratory studies the role of physiological and pathological mechanical stimulation in the regulation of lung endothelial cytoskeletal remodeling and lung permeability. He has established in vitro models of lung cells exposed to shear stress and cyclic stretch and demonstrated a role for Rac-mediated signal transduction in the cortactin-mediated enhancement of endothelial peripheral actin cytoskeleton associated with barrier-protective response to laminar flow or physiological cyclic stretch. He has shown the differential effects of low and high magnitude cyclic stretch relevant to ventilator induced lung injury on lung endothelial cell signaling, phosphorylation of regulatory proteins, and lung permeability responses. In this project, he elucidates the involvement of small GTPases Rac and Rho in the cytoskeletal regulation of endothelial barrier and specific interactions between focal adhesion and adherens junction complexes in stretch-mediated endothelial barrier regulation. The other major focus in his laboratory is elucidation of the role of specific components of oxidized phospholipids (OxPL) in the modulation of the lung vascular leak and lung inflammation induced by edemagenic and pro-inflammatory stimuli. His laboratory recently discovered a novel barrier-protective effects of oxidized phospholipids on lung endothelium and reported Rac/Cdc42-mediated mechanisms of their action. In this study, he focuses on the role of focal adhesions and adherens junctions in the barrier regulation by OxPL. In addition, his laboratory studies anti-inflammatory effects of OxPL on septic and aseptic lung injury. He expects these studies will identify potential novel barrier-protective targets for drug design.

Joe G.N. Garcia, M.D.

Dr. Garcia is a leading authority on lung biology and disease, the genetics of acute lung injury and the molecular mechanisms of edema formation, a process also termed vascular leak. Vascular leak occurs when blood cells and fluid escape from blood vessels into the surrounding tissues, including the lungs. This follows acute injury or infection and occurs in response to the stresses of mechanical ventilation. When severe, flooding of the lungs often leads to organ damage or death. Dr. Garcia's studies of the basic biology of this process have focused on signal transduction pathways and the cytoskeleton of the endothelium. Results from Dr. Garcia’s lab have led to novel approaches to prevent vascular leak, reduce physiologic derangements and restore the integrity of vessel walls.

Kimm Hamann, Ph.D.

Dr. Hamann's research focuses primarily on the role of the TNF family death receptors, particularly Fas/CD95 and the TRAIL (TNF-related apoptosis-inducing ligand) receptors, in hematopoiesis and inflammation, and on the mitochondrial pathway of cell death in ischemia/reperfusion injury of cardiomyocytes. Studies currently are focused on inflammatory cells (such as eosinophils), whose numbers increase dramatically and chronically in certain disease states, and examine the role(s) of apoptosis in both the production (hematopoiesis) of these cells and the resolution of eosinophilic inflammation. Further, he is examining the expression of FasL by airway epithelial cells and their interactions with eosinophils in pulmonary inflammatory states such as asthma. Additional asthma-related studies include investigations of corticosteroid and beta-agonist effects on inflammatory cell apoptosis, and the effects of therapeutics on molecular pathways involved in cell survival. As another major and related focus of our laboratory, he is investigating Fas-mediated, "downstream" activation of the nuclear transcription factor, NF-kB, and the role of its gene targets in apoptosis of both inflammatory cells. In cardiomyocytes, we currently are studying molecular mechanisms of apoptosis and "preconditioning"-induced protection against apoptosis, including NF-kB-mediated events, and involvement of protective molecules.

Jeffrey Jacobson, M.D.

Derangements in lung vascular permeability, particularly in the context of acute inflammatory lung injury (ALI) and ventilator-associated lung injury (VALI), represent a common yet difficult clinical problem associated with significant morbidity and mortality. Regrettably, effective therapies are currently not available and novel molecular targets and therapeutic strategies are desperately needed. The statins are a class of HMG-CoA reductase inhibitors used clinically to lower serum lipid levels and reduce the morbidity and mortality associated with coronary artery disease. However, not all beneficial effects of statins can be attributed to cholesterol lowering with mounting evidence suggesting a favorable impact in a variety of clinical disorders. Accordingly, his research have hypothesized that, via complex effects on endothelial cells, simvastatin offers a novel therapeutic, barrier- protective strategy for ALI/VALI. Consistent with this hypothesis, he has recently reported that simvastatin promotes EC barrier function in vitro and in vivo, even in the presence of edemagenic agonists, a finding with dramatic significance with respect to clinical conditions characterized specifically by increased vascular permeability such as ALI/VALI. Further characterization of these effects, the underlying mechanisms by which simvastatin augments EC barrier function, and relevance to other clinical conditions including ischemia-reperfusion lung injury, are the focus of our ongoing research.

Irina Kolosova, Ph.D.

Dr. Kolosova’s research is devoted to barrier properties of pulmonary endothelium under normal and pathological conditions. Inflammatory agonist-induced endothelial dysfunction is associated with cytoskeletal remodeling, disruption of cell-cell contacts and the formation of paracellular gaps leading to vascular leak and edema formation. Dr. Kolosova uses a monolayers of cultured endothelial cells as a model system for functional and biochemical studies of barrier properties. Her recent interest is focused on the mechanisms of endothelial barrier protection and finding strategies to preserve barrier integrity. Specifically, she has demonstrated that purines (adenosine triphosphate and its synthetic analogs) caused profound enhancement of transendothelial barrier via receptor-mediated G protein activation. The goal of the ongoing study is to characterize downstream signaling pathways leading to endothelial barrier enhancement as well as to explore therapeutic potential of purines in murine model of acute lung injury.

Ratnesh Lal, Ph.D.

Dr. Lal is an authority on biomedical applications of atomic force microscopy (AFM). Research in his lab involves the development of nanotechnologies for and multi-scale biophysical and system biology studies of channels and receptors. Hemichannel study has defined its role in apoptosis, arrhythmias, and cancer. Amyloid ion channel study had provided a paradigm shift for the study of protein misfolding diseases (e.g., Alzheimer�s, Parkinson�s Diseases, ALS, many systemic amyloidogenic diseases). His lab also designs nanosensors and devices for biomedical diagnostics and therapeutics.

Alan Leff, M.D.

Dr. Leff's research is conducted through the Airway Biology Research Group, which is a federally funded center for structured multidisciplinary collaboration of MD, and PhD investigators who are appointed in the Departments of Medicine and Pediatrics, and whose central interest is in the cellular pathophysiology of asthma and the maturational development of airway cells and tissues. A major direction of this work is focused upon the inflammatory induction of airway hyperresponsiveness. These studies utilize ferromagnetically isolated peripheral human eosinophils and eosinophils cultured from pluripotential human umbilical cord blood to study the effects of cytokines, particularly IL-5 and GM-CSF and inflammatory mediators (especially platelet activating factor) on eosinophil function in guinea pig airway. Studies directed by Kimm Hamann, PhD have focused on the expression of eosinophil adhesion molecules and the adhesion and migration of these cells to cultured endothelial cells. Additional studies have focused upon epithelial activation and secretion and cell-cell communication of epithelium with underlying airway smooth muscle (Nilda Munoz, Senior Research Scientist). This work currently involves the characterization of the potential mediators of epithelial inhibition/secretion and utilizes two different primary cultures of epithelium. A further application of this work is the influence of inflammatory mediators, especially the major basic protein of eosinophils, on epithelial cell metabolism and the role of activated, isolated human eosinophils in transduction of epithelially mediated hyperresponsiveness in the guinea pig. A second area of investigation is the mechanism of signal transduction in eosinophils. Studies are being conducted to determine the relationship between molecular adhesion molecules and the pregulation of stimulated secretion from eosinophils during diapedesis and migration into bronchial airways. These studies have lead to the observation that cytosolic PLA2 appears to be the essential messenger protein in all integrin adhesion (Xiangdong Zhu, MD). Further studies are investigating the role of secretroy PLA2 in inflammatory cells. A fourth area is investigation of the relationship of Th2 helper cells to augmented secretion from human eosinophils. These studies, conducted with Anne Sperling, PhD, Ms. Munoz and Dr. Ivor Douglas examine the role of molecular adhesion molecules on Th2 cells in the upregulation of the secretion of bronchoactive mediators from eosinophils.

Shwu Fan Ma, Ph.D.

Acute lung injury is a complex illness with high mortality rate (> 30%) and often requires the use of mechanical ventilatory support for respiratory failure. Mechanical ventilation can lead to clinical deterioration due to augmented lung injury in certain patients, suggesting the potential existence of genetic susceptibility to mechanical stretch, the nature of which remains unclear. To identify genes affected by ventilator-induced lung injury (VILI), Dr. Ma examines gene expression profiles of VILI models using the oligonucleotide microarray platform and the combination of multiple bioinformatics web-tools (e.g. Robust Microarray analysis, significance analysis of microarray, GenMAPP and MappFinder etc.). She is also interested in identify the genetic modifiers in acute lung injury. For this study, she examines the candidate gene polymorphisms which could be responsible for the susceptibility to either sepsis related acute lung injury or sepsis itself. Her studies are concentrated on the analysis of ALI-independent allelic variants that are generic for sepsis, as well as allelic variants associated with mechanical ventilation related morbidity and mortality. Progress in understanding of cardiopulmonary diseases heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide new insights into pathogenesis and treatment of these pathologies.

Jaideep Moitra, Ph.D.

Dr. Moitra’s research interests revolve the central problem of transcriptional regulation of eukaryotic genes from various angles that has included studying the structural biology of bZIP transcription factors to applying the experimentally observed structural rules for designing synthetic dominant negatives (DNs) to overexpressing such DNs in mice.
Adipose tissue specific expression of a designed bZIP DN resulted in mice that had no white fat, and greatly reduced or inactive brown fat. These mice were severely diabetic, and resembled the human disease of lipoatrophic diabetes. This result resulted in Dr. Moitra’s interest in modeling human diseases in mice by genetic modifications. The current projects with the MYLK gene that he is involved in the laboratory of Dr. Joe G.N. Garcia are directly related to my basic research interests in transcriptional regulation and disease modeling in GM mice.

Liliana Moreno, Ph.D.

One of Dr. Moreno’s main interests is to find new and effective intervention strategies for cardiopulmonary disorders such as acute lung injury and pulmonary hypertension by developing small animal models of diseases. For example, lung ischemia-reperfusion lung injury, a common sequelae to lung transplantation, for the administration and validation of vascular barrier-protective compounds. In pulmonary hypertension, by generating different rodent models of disease, for administering different therapeutic approaches such the use of stem cells and compounds that prevent or restore vascular leak. Ultimately developing these models in different strains will help to elucidate genetic and molecular mechanisms, which will have a positive impact in lung diseases.

Viswanathan Natarajan, Ph.D.

Dr. Natarajan is a well established and leading investigator on vascular biology, oxidant-induced lung injury, mechanisms of regulation of phospholipases A2 and D and generation of lipid second messengers such as oxygenated derivatives of arachidonic acid, phosphatidic acid and lysophosphatidic acid in the lung and role of bioactive lipids as modulators of airway inflammation and endothelial cell homeostasis. Dr. Natarajan’s laboratory has been actively investigating the role of NADPH oxidase sub-components and its homologs in production of reactive oxygen species leading to vascular leakiness and cross-talk between G-protein coupled receptors and growth factor receptors in lysophosphatidic acid mediated cytokine secretion and innate immunity. This translational research will lead to development of novel therapeutic interventions to reduce airway inflammation and pulmonary edema.

Yimin Qin, M.D.

Dr. Qin is primarily interested in the mechanisms and consequences of Tumor Necrosis Factor (TNF) receptor super family induced NF- B transactivation in human eosinophils. This research has been mainly focused on: Determine whether ligation of Fas by Fas ligand induce apoptosis or promotes survival through Fas-mediated NF- B transactivation in human eosinophils; Examine NF- B-regulated expression of anti-apoptotic proteins including IAPs, Bcl-2 family and FLIPs upon Fas/FasL ligation in Eosinophils; Investigate the relationship between these NF- B regulated genes expression and Eosinophils accumulation in autoimmune diseases, specially asthma. Dr. Qin's secondary interest is to study the signal transduction pathway of NF- B transactivation and its target genes expression during hypoxia-induced preconditioning in cardiomyocytes, and to define the role of NF- B transactivation in suppression of Ischemia/Reperfusion-mediate cardiac injury.

Julian Solway, M.D.

Julian Solway, MD has a long-standing interest in mechanisms underlying airway constrictor hyperresponsiveness in asthma. The Solway laboratory now addresses four issues related to this overall topic: 1) Molecular regulation of contractile protein accumulation in airway smooth muscle, with emphasis on the nuclear trafficking of serum response factor and on the role of GATA5. 2) Evaluation of the mutations and consequent pathophysiological mechanisms underlying heritable cholinergic airway hyperresponsiveness in a kindred of chemically mutagenized mice. 3) Exploration of the functional genetics of asthma, with focus on the pathogenetic consequences of genetic variations associated with asthma, and on analysis of airway smooth muscle microdissected from endobronchial biopsies of asthmatic or normal volunteers. 4) Identification of the molecular mechanisms that regulate the mechanical plasticity-elasticity (taffy-like vs. rubber band-like) balance in contracted airway smooth muscle.

Anne Sperling, Ph.D.

Dr. Sperling's laboratory is interested in the role of costimulatory and accessory receptors on the regulation of T cell activation and function in Th2-mediated inflammatory responses.

Her work focuses on studying the novel CD28 family member, ICOS. ICOS was originally described as a Th2 specific costimulatory molecule. She has found that ICOS costimualtion regulates Th2 inflammation in a model of asthma. This regulation is at the level of clonal expansion and migration into lymph nodes. The potential of ICOS to regulate effector functions in murine models of allergic airway disease has lead to the speculation that interfering with ICOS-B7RP-1 interactions may provide a novel mode of immunotherapy for allergic asthma as well as autoimmune diseases. New data from her laboratory with human subjects suggest that ICOS expression levels are associated with allergic responses. Together these data suggest that ICOS plays a key role in the regulation of Th2 immune responses.

Another accessory receptor that we are actively studying is the large cell surface mucin, CD43. CD43 is unarguably one of the most abundant proteins on the T cell surface. It has been estimated to cover up to 28% of the surface area on T cells. However, the literature is full of seemingly contradictory findings on the function of this molecule. She has found that the large mucin is actively excluded from T cell/APC interaction sites by linking to the actin cytoskeleton through the Ezrin-Radixin-Moesin (ERM) family of cytoskeletal adaptor proteins. Blocking this movement effects T cell cytokine production and effector function. Further structure-function studies are underway to determine the role of this abundant molecule in the immune response.

Steven White, M.D.

Dr. White's interests include the repair and survival of airway epithelium in asthma and airway inflammation. He examines the role of cytokines and corticosteroids in programmed cell death, cell-matrix interactions in cell migration, and the expression of adhesion receptors. Recent areas of emphasis include the role of the actin cytoskeleton as a modulator of early events in apoptosis and the role of transforming growth factor beta as a regulator of airway epithelial cell survival.

Fernando Teran Arce, Ph.D.

Dr. Arce is interested in biophysical applications of scanning probe microscopy, primarily the atomic force microscopy. His current research involves the application and further development of atomic force microscopy based mapping of force and physical energy in living biological systems ranging from isolated macromolecules to membrane, cells and tissue. He is also investigating the structure, as well as structure/function relationship, of trans-membrane proteins reconstituted in supported lipid bilayers. Furthermore, he is extending these studies to the case of lipid bilayers separating two aqueous compartments. The development of nanosensors for the detection of single ion channels is envisioned as application of the latter work.

Peter Usatyuk, Ph.D.

Dr. Usatyuk’s investigations include work in the area of oxidative stress and role of oxidants in endothelial barrier function involving calcium signaling, cytoskeletal reorganization, focal adhesions and adherens junction proteins and protein tyrosine kinases. Additionally, his interest includes hyperoxia-induced endothelial cells barrier function and cytoskeletal regulation of NADPH oxidase. He also collaborates on research projects that investigate agonist-induced calcium signaling in the lung. His future studies will focus on signaling pathways that modulate cross-talk and interaction between focal adhesion and adherens junction proteins to better understand the pathophysiology of vascular leak and lung injury.

Li Qin Zhang, Ph.D.

Dr. Zhang is interested in the identification of Pre-B-cell Colony Enhancing Factor (PBEF) functional domains in the context of the endothelial barrier regulation; dissection of signal transduction pathways in the PBEF-mediated endothelial barrier dysregulation; and validation of the in vivo role of PBEF promoter SNPs to the susceptibility to acute lung injury (ALI) in murine models. She is also interested in the study of molecular events and pathways involving PBEF in the differentiation of dendritic cells.

Yutong Zhao, Ph.D.

Dr. Zhao’s research is focused on investigating the role of lysophosphatidic acid (LPA) and lipid phosphate phosphatases (LPPs) in airway inflammation and innate immunity. An important finding of his work has been that LPPs regulate LPA-induced IL-8 gene expression and secretion in human bronchial epithelial cells by modulating intracellular calcium release and NF-?B activation. Additionally, Dr. Zhao is also interested in the role of interaction and cross-talk between G-protein coupled LPA receptors and growth factor receptors in airway inflammation.

Xiangdong Zhu, Ph.D.

Dr. Zhu's research is focused on the role of eosinophil adhesion and transmigration in the pathophysiology of asthma. My studies demonstrated that eosinophil adhesion to vascular endothelial cells and transmigration into the asthmatic airways is regulated by a cytosolic 85-kDa phospholipase A2 (cPLA2). These studies have lead to the observation that cPLA2 serve as a messenger protein in regulating integrin function, in addition to its role in lipid inflammatory mediator synthesis. Further studies are to characterize the upstream signaling components in cPLA2 mediated eosinophil adhesion. The focus will be on MAP kinases, phosphoinositide 3 kinase, and small GTPase Ras.

Blanca Camoretti-Mercado, Ph.D.

Dr. Camoretti-Mercado is interested in the fundamental aspects of normal and disease muscle function at both cellular and molecular level. Her final goal is to understand the pathogenesis of asthma and LAM diseases in order to develop therapeutic agents to treat (and cure) these disorders. She applies molecular, genomic, genetic, cellular, immunological, proteomic, and physiological approaches in her studies.

Specifically, she wants to elucidate the molecular mechanisms that control specific gene expression in airway smooth muscle using a variety of gene markers; how it is modulated in health and disease with special focus on SRF (Serum Response Factor) activity. How myocytes influence other resident and inflammatory cells in the lung; and conversely, how muscle functions (proliferation, survival, gene expression, and migration) are altered by other type of cells and their cells products.