Researchers at Weill Cornell Medical College were awarded a $6.5 million grant from the National Heart, Lung, and Blood Institute to conduct a 5-year long research project into metabolic changes that occur in the lungs epithelial cells’ in patients with chronic obstructive pulmonary disease (COPD) patients due to cigarette smoking. The team will also aim to investigate which cigarette smokers have the highest risk of developing COPD and try to identify new biomarkers that will be of benefit in developing new therapies for the disease.

Even though smoking is a major cause of disease, such as COPD, and is the fourth highest cause of mortality, one-fifth of the adult population still continue to smoke, and with each inhalation, the lungs are burdened with a hundred trillion oxidants and over 4,000 chemical compounds. There is still no cure for COPD, and no biomarkers that can diagnose the disease early. The only treatment available for those suffering from COPD is oxygen therapy.

Leading researcher, Dr. Ronald G. Crystal, chairman of genetic medicine at Weill Cornell Medical College, declares:

“Twenty percent of smokers get COPD, so it is vital that we identify who is at the highest risk and why. 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.”

Patients that developed COPD due to smoking are often short of breath and the severe narrowing of the airways within the lung results in loss of lung function. COPD is also linked to the progression of “ciliopathy.”

Most epithelial cells in the lung’s airway consist of cilia, i.e. important cells to maintain a healthy lung, which are vital in transporting mucus and any inhaled pathogens like bacteria, up the airway and out of the lungs to prevent infection. Ciliopathy is a cellular dysfunction within the airway epithelial cells, which leads to mucus accumulation, shortened cilia cells, and impaired defenses against infection.

Co-principal researcher, Dr. Steven S. Gross, professor of pharmacology and director of the Mass Spectrometry Facility at Weill Cornell explains:

“Ciliopathy occurs long before there are any clinical signs of smoking-induced COPD. However, the underlying genesis of smoking-induced airway ciliopathy is unknown. The goal of our study is to fill this knowledge gap and identify what exactly drives ciliopathy in smokers with COPD.”

According to the researchers, hypothesis ciliopathy is associated with oxidant stress that smoking deposits on airway epithelium cells and smoking-induced COPD is linked to a changed metabolism in lung tissue and serum. They believe that profiling metabolites in COPD patients’ biofluids will offer a better understanding of the underlying molecular mechanisms of developing ciliopathy as well as COPD’s pathogenics.

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

For their new research project, the team will for the first time use metabolomics to broadly identify, examine and profile abnormal variations in cell metabolism and metabolites for COPD in the airway of epithelial lung cells. They will examine thousands of small molecules, measuring changes in metabolite expression by using the most advanced technology based on mass spectrometry to help in global metabolite profiling COPD patients’ lung serum and tissue samples. Cell metabolism is various chemical reactions that occur within the cell, whilst metabolites are their small molecule products, which are involved all aspects of cellular function.

Dr. Gross states: “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. Global metabolite profiling represents an untapped route for defining which biochemical pathways are specifically altered in smokers with COPD.”

The researchers will also combine metabolic profiling with in vitro studies of human subjects and murine airway epithelium. In the study they will analyze 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 and compare these to different types of populations, including smokers, non-smokers, smokers with and without COPD smokers and smokers with COPD who stopped smoking.

Written by Petra Rattue