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Researchers at Weill Cornell Medical College were awarded a $6.5 million grant from the National Heart, Lung, and Blood Institute for a five-year investigation into metabolic changes occurring within airway epithelial cells in the lungs of chronic obstructive pulmonary disease (COPD) patients caused by cigarette smoking. In addition, researchers aim to identify which cigarette smokers are at highest risk of developing COPD as well as novel biomarkers to assist in the development of new therapeutic treatments for the disease.

One-fifth of the adult population in the United States smokes cigarettes, and each puff can burden the human lungs with a hundred trillion oxidants and more than 4000 chemical compounds. Cigarette smoking is a major cause of disease, including COPD, the fourth leading cause of death of Americans. There is currently no cure, no effective treatments beyond oxygen therapy and no biomarkers to diagnose the disease early.

"Twenty percent of smokers get COPD, so it is vital that we identify who is at the highest risk and why," says Dr. Ronald G. Crystal, co-principal investigator for the study and chairman of genetic medicine at Weill Cornell Medical College. "Gaining a better understanding of COPD's underlying biology and the metabolic changes forced by cigarette smoke to airway epithelial cells will help us effectively deal with this major health problem. We can use this information to develop new ways to protect the lungs."

Smoking-induced COPD patients can experience shortness of breath and loss of lung function due to the severe narrowing of their lung airways. COPD is associated with the progression of "ciliopathy," the cellular dysfunction within the airway epithelial cells that leads to the shortening of cilia cells, mucus accumulation and the impairment of infection defenses. The majority of epithelial cells are made up of cilia, important cells in lung health that play the crucial role of moving mucus and any inhaled pathogens, such as bacteria, up and out of the lungs to prevent infection.

"Ciliopathy occurs long before there are any clinical signs of smoking-induced COPD. However, the underlying genesis of smoking-induced airway ciliopathy is unknown," says Dr. Steven S. Gross, co-principal investigator of the study and professor of pharmacology and director of the Mass Spectrometry Facility at Weill Cornell. "The goal of our study is to fill this knowledge gap and identify what exactly drives ciliopathy in smokers with COPD."

The researchers hypothesize that ciliopathy is linked to the oxidant stress placed on airway epithelium cells by cigarette smoke and that smoking-induced COPD is associated with altered metabolism in lung tissue and serum. Researchers believe the profiling of metabolites in the biofluids of COPD patients will provide fundamental insight into the underlying molecular mechanisms of ciliopathy development and the pathogenesis of COPD.

"A biomarker for COPD would be useful to identify smokers that will develop COPD," says Dr. Crystal. "Success of this study would be a major step in developing new approaches for the screening and treatment of COPD patients."

In the study, Weill Cornell researchers will for the first time use metabolomics to broadly identify, analyze and profile abnormal changes in cell metabolism and metabolites for COPD in the airway of epithelial cells in the lungs. Using the latest state-of-the-art mass spectrometry based technology to assist in global metabolite profiling of lung serum and tissue samples of COPD patients, researchers will examine thousands of small molecules and measure changes in metabolite expression. Cell metabolism is the set of chemical reactions that occur inside the cell and metabolites are their small molecule products that participate in all aspects of cellular function.

"The use of metabolomics is a powerful new approach to discover how airway epithelial cells are disturbed by smoking and how this may lead to COPD," says Dr. Gross. "Global metabolite profiling represents an untapped route for defining which biochemical pathways are specifically altered in smokers with COPD."

In addition, researchers will combine metabolic profiling with in vitro studies of human subjects and murine airway epithelium. Serum, lung epithelial lining fluid and airway epithelium samples from human research subjects, as well as an extensive cohort of banked human clinical trial samples, will be analyzed and compared from a population of nonsmokers, smokers, COPD smokers and smokers with and without COPD that underwent smoking cessation.

The study is a collaboration between Weill Cornell and Cold Spring Harbor Laboratory. Other study investigators include: Dr. Yuliang Ma, Dr. Jason G. Mezey, Dr. Matthew Walters from Weill Cornell; and Dr. Grigori N. Enikolopov and Dr. Natalia Peunova from Cold Spring Harbor.

Weill Cornell's new award is part of a larger grant awarded to five institutions chosen to receive funding from the National Institutes of Health (NIH) to study the abnormal metabolism of cardiovascular and lung diseases. The five partnering institutions include: Washington University, Cleveland Clinic, Emory University, National Jewish Health and Weill Cornell. Washington University will serve as the coordinating center for the research program. The researchers from the five institutions will work together and with the NIH to inform new approaches and new ideas in each other's studies.

This work is supported by the NHLBI with NIH grant number P20HL113443.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.