The Division of Pulmonary and Critical Care Medicine is distinguished for its world-renowned investigators in multiple areas, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and idiopathic pulmonary fibrosis (IPF).
Under the direction of Dr. Fernando J. Martinez, Chief of the Division of Pulmonary and Critical Care Medicine, critical lines of research are underway in the field of lung disease. Recognized nationally and internationally as a premier leader in his field, Dr. Martinez has established a robust translational research program in COPD and IPF that has been NIH funded since its inception more than two decades ago. His research on COPD focuses on the disease's appropriate and early diagnosis, biological underpinnings and personalized approaches to innovative therapeutic strategies. As a key participant in numerous NHLBI-sponsored COPD studies, Dr. Martinez has defined the role of lung volume reduction surgery, chronic macrolide therapy, statin therapy, and long-term oxygen therapy. He has also been involved in defining the immunological basis of acute exacerbations, the role of innovative small airways imaging methods, and the role of COPD endotypes. Within the world of fibrosing lung diseases, he refined the optimal approaches to diagnosing idiopathic interstitial pneumonias, defined the imaging and biochemical approaches to prognostication, and has investigated the role of various therapeutic approaches to IPF. In recent years, Dr. Martinez has focused on the interaction between dysbiosis in the lung microbial community and disease progression. He is the principal investigator of an NIH sponsored, multi-center clinical trial testing the concept that antimicrobial therapy can equilibrate the lungs microbial community resulting in improved clinical outcomes.
Dr. Augustine M.K. Choi's laboratory made the seminal discovery that CO, a noxious gas, known to be lethal at high doses or due to environmental exposure, can have potent biological effects at physiological concentration. His laboratory has led the investigative community in revealing that CO mediates the anti-inflammatory effects through upstream signaling pathways, including mitogen-activated protein kinase pathways, and by inhibiting Toll-like receptor signaling. This finding, that a gaseous molecule produced endogenously by cells can exert anti-inflammatory effects, opened new avenues of research in both experimental models of clinical disease and in human disease. Dr. Choi's studies have since demonstrated that low dose inhaled CO exhibited potent anti-inflammatory effects in numerous preclinical models of human disease. His laboratory employs state-of-the-art techniques (e.g. genomic approaches) to identify candidate genes in the pathogenesis of lung diseases and is illuminating the role of autophagy in acute and chronic lung diseases. Dr. Choi has led the investigative community in the design and successful completion of Phase I and Phase II trials regarding the use of inhaled CO in human diseases.
Dr. Robert Kaner serves as the co-Principal Investigator of the New York Presbyterian site of the Pulmonary Fibrosis Foundation Care Center Registry. He was the site PI of Idiopathic Pulmonary Fibrosis (IPF) Clinical Research Network, where he chaired the Adjudication Committee for IPFnet, and in that capacity, has collaborated productively with Dr. Fernando Martinez. He is the project leader of an NIH-sponsored study of the molecular basis of accelerated emphysema development in HIV-1 positive smokers. He has served as Principal Investigator of an NIH-sponsored basic research study on the mechanisms of vascular permeability in the lung and interactions of human alveolar macrophages with HIV-1. He has also studied severe sepsis and nosocomial pneumonia. Dr. Kaner's research is noted for the application of cutting-edge molecular techniques, such as phenotyping in patients with lung diseases. Dr. Kaner's work has identified matrix metalloproteinase upregulation in the lung as a potential contributor to early emphysema in HIV-positive individuals. He and collaborators within the infectious disease division are currently enrolling subjects in a pilot study to determine if doxycycline can reduce lung matrix metalloproteinase activity in HIV-positive individuals with COPD and/or emphysema. He has shown that high levels of VEGF protein are compartmentalized to the epithelial lining fluid in normal humans. Regarding the role of mast cells in fibrogenesis in IPF, he found that human lung fibroblasts upregulate collagen synthesis in vitro via release of both histamine and renin.
Dr. Michael Niederman is an international authority on respiratory infections. He has been engaged globally in the development of diagnostic and therapeutic guidelines for the management of community acquired and hospital acquired pneumonias. He has an active investigative portfolio examining novel therapeutic options for respiratory infections, including complex respiratory infections in the intensive care unit. He is currently leading an international multi-center study of the use of adjunctive aerosolized antibiotics for the therapy of severe pneumonia. He is also focused on an investigative portfolio leveraging antimicrobial stewardship by enhancing the optimal therapeutic approach to respiratory infections in the ICU while minimizing antimicrobial resistance.
Dr. Hasina Outtz Reed studies the role of the pulmonary lymphatic vasculature on chronic lung disease and lung homeostasis. While it has been known for quite some time that lymphatics are present and likely important for lung function, tools for testing whether the lymphatics play a role in lung pathology and for targeting these vessels have been lacking. Dr. Outtz Reed has developed novel mouse models for impaired pulmonary lymphatic flow and is among the first to have shown a direct connection between lymphatic dysfunction and lung injury. Ongoing work will investigate how underlying lymphatic dysfunction affects the lung’s response to injury and the mechanism by which it occurs. Furthermore, her work will develop innovative methods for imaging and modifying the pulmonary lymphatics with the hope that these tools will translate to the ability to target these vessels therapeutically.
Dr. Renat Shaykhiev, who recently joined the pulmonary division, is focused on airway epithelial stem cells, differentiation pathways and plasticity; epithelial-mesenchymal interactions, using 3D airway organoid models that mimic organization of human airways in the in vivo lung; epithelial-immune interactions and innate immunity in the lung; and pathogenesis of airway remodeling in human lung disease. The latter line of study uses patient-derived models of airway epithelial differentiation and remodeling to study the molecular and cellular mechanisms that underlie the early pathogenesis of airway remodeling in human lung diseases, such as COPD, asthma, pulmonary fibrosis and lung cancer.
Dr. Suzanne Cloonan, who collaborates closely with Drs. Choi and Martinez, studies programmed cell death (PCD) pathways in the pathogenesis of disease states. She first identified a non-canonical form of PCD involving autophagy as a mechanism of action pertaining to particular anti-depressant drugs. Her advances in research include: showed a mechanism by which cilia of the airway epithelium shorten in response to cigarette smoke as related to COPD pathogenesis; showed in vitro and in vivo, that cigarette smoke induces mitochondrial dysfunction in the lung, leading to selective removal of mitochondria by PINK-1 dependent autophagy or mitophagy; and identified a GWAS COPD susceptibility gene in the regulation of mitochondrial responses to cigarette smoke.
Dr. Heather Stout-Delgado, who collaborates closely with Drs. Choi and Martinez, focuses on the impact of aging on innate immune responses to bacterial and viral pulmonary infections. Her laboratory is also examining how the process of biological aging and dysregulated molecular signaling pathways can contribute to the development of pulmonary fibrosis. Using both in vitro and in vivo models, her laboratory is critically examining cellular and molecular signaling cascades with the goal to design therapeutic strategies to improve these responses in the aged lung.
The Critical Care section of the Division of Pulmonary and Critical Care Medicine is at the forefront of advances in research that are benefiting the clinical care setting, such as the Intensive Care Unit. Studies underway cover a wide breadth, from sepsis to lung and brain injury, and are carried out by individual investigators or in collaboration with outstanding researchers from other divisions within the Weill Department of Medicine.
Dr. Choi is currently conducting two FDA approved Phase II clinical trials investigating both sepsis and IPF. Regarding the treatment of sepsis-induced ARDS (acute respiratory distress syndrome), he is leading an NIH-sponsored Phase I trial.
There are numerous other lines of sepsis study in the division, that include: the role of heart rate variability in early sepsis, the role of the endothelium and coagulation, symptom management in critically ill patients, the role of endothelial micro-particles, and the roles of autophagy, mitochondrial DNA and the inflammasome.
Drs. Ed Schenck, Maria Pabon, Kiichi Nakahira, John Arbo, and David Berlin lead a biobank of critical illnesses. The registry contains detailed phenotypic information and biologic specimens with a focus on the evaluation of damage-associated molecular patterns in critical illness.
Additional investigations in the area of critical care include: physiology of cardiac output monitors and novel ventilation strategies, the outcomes of difficult airway management and bronchoscopy in critically ill patients, physiology of cardiac output monitors and novel ventilation strategies, clinical significance of hemodynamic waveforms, models of ventilator induced lung injury, and ischemic-anoxic brain injury.
Dr. Michael Niederman, the Division of Pulmonary and Critical Care Medicine Clinical Director, is leading a study on ventilator-associated pneumonia.
Critical Care Medicine: Aging – Pulmonary Infections and Pulmonary Fibrosis
As the population continues to live longer in the U.S., the division remains focused on pulmonary infections and pulmonary fibrosis as related to aging. Influenza viral infections are responsible for annual epidemics that cause severe morbidity and mortality worldwide. It is imperative to elucidate how aging modifies innate immunity and contributes to viral persistence and increased susceptibility to secondary bacterial infections. Researchers in the division are investigating the impact of biological aging on innate immune responses to primary viral and bacterial pulmonary infections, with the goal to design and evaluate therapeutics to improve these responses in the aged lung.
Aging is associated with declined mitochondrial energy metabolism, enhanced mitochondrial oxidative stress, increased production of mitochondrial reactive oxygen species (mtROS), and accumulated mitochondrial DNA mutations. Low levels of inflammation, due to enhanced mitochondrial dysfunction and oxidative stress, can potentiate inflammatory responses associated with many age-related degenerative diseases. Fibrotic interstitial lung diseases, which are severe and progress rapidly, and include idiopathic pulmonary fibrosis (IPF), are more prevalent in aging populations. A sharp increase is seen in these diseases for those older than 50 years.
Little is known of how oxidative stress, mitochondrial dysfunction and the process of aging may contribute to disease pathogenesis. Researchers in the division are investigating the cellular and molecular pathways that underlie enhanced fibrotic lesion development in aged lungs, with the goals of designing and evaluating therapeutic treatment strategies to improve lung function in older populations.