Cigarette smoking is a leading cause of chronic cough (popularly known as smoker’s cough), which may lead to breathing difficulties in one of five smokers. It has always puzzled the investigators and researchers how 80% smokers evade complications from long-term smoking like chronic obstructive pulmonary disease (COPD), while 20% succumb to moderate to severe airway damage, culminating in high morbidity and mortality. It has been estimated that COPD is the third most common cause of death in United States.
It was proposed long ago that genetic make up may explain how different people respond to hundreds of toxins and chemicals released into the body of a smoker; however, the details of the responsible genes remained a mystery until research conducted by scientists at Weill Cornell Medical College explained the pathogenesis of COPD, and how some genetically susceptible individuals develop compromised pulmonary functioning.
Details of the Study:
The team of investigators at Weill Cornell Medical College enrolled 20 subjects in the study. 50% of the study population was comprised of smokers, while the other 50% were non-smokers. Both study groups were examined and lung functions were labeled as healthy in both the groups on the basis of absence of physical findings in history or examination, chest x-rays, and pulmonary function tests.
The research team then obtained basal cell samples from both the groups by using fiberoptic bronchoscopy (a specialized instrument that collects bronchial secretions and airway samples with great precision and accuracy) and conducted genomic sequencing on the basal cells obtained. As part of the genomic sequencing, messenger RNA was studied (an integral element in the process of protein synthesis from genetic expression) and it was observed that expression of 676 genes was altered in smokers.
The Chairman of genetic medicine at Weill Cornell Medical College, Dr. Ronald G. Crystal, explained: “Smoking essentially reprograms basal cells to have an output of messenger RNA that is different from that of non-smokers.”
The research conducted on COPD smokers as well as healthy smokers explained that 4 key genes are abnormally expressed in the basal progenitor cells of lung parenchyma (also known as airway basal cells), which plays a critical role in normal pulmonary functioning.
The scientists identified a total of 676 genes that were linked to abnormal genetic expression in the basal cells of pulmonary epithelium. The four critical genes were among the first to affect the integrity of basal cells in chronic smokers leading to COPD.
Dr. Ronald G. Crystal explained:
“This is the first demonstration of COPD risk genes to an actual mechanism within cells that are critical for the maintenance of lung health. We doubt these four genes are completely responsible for COPD. They are likely part of the story — we believe they play a central role in the very early events that lead to COPD, but they act within a very complex genetic-environment interaction.”
Investigators also explained why some smokers develop COPD while others remain symptom-free. The abnormality in the genetic expression of four genes that were linked to COPD is not uniform in all smokers (like other genes), which may explain the inherent tendency of some smokers to develop COPD.
Dr. Crystal noted that the toxins and chemicals present in cigarette smoke have a tendency to reprogram basal cells. Individuals who are carriers of certain genes are more susceptible to this reprogramming, but the exact details are not yet known.
Basal cells are the lining cells of pulmonary epithelium that constitutes 5 to 15% of the cellular population of pulmonary airways and the wind-pipe. Basal cells act as the stem cells to generate other specialized varieties of pulmonary cells to serve different functions.
Dr Crystal, who is also the senior investigator of the study, explained that pulmonary lining cells are continuously replaced by specialization of basal cells in case of any toxin or chemical mediated damage or cell death. However, when basal cells are re-programmed or compromised, the lungs have no other method of the restoration of lung function. He also suggested that knowing the critical processes that may affect the genetic expression in some individuals may help in protecting lung damage in susceptible smokers (possibly by switching or turning off the genes).
The scientists also identified that approximately 25% of the gene population (or 166 genes) were linked to chromosome 19 (that is very frequently associated with COPD). Moreover, 13 genes were present on the precise gene locus of chromosome 19 i.e. 19q13.2 (four of which are already known to be linked to COPD).
The research also explained that pulmonary changes due to re-programming of basal cells takes time to produce measurable and identifiable results and smoker may remain healthy for a significant period of time.