New Clues to COPD Linked to Proteostasis Imbalance Caused by Cigarette Smoke

Since the identification of factors contributing to the development of COPD is crucial for developing new treatments, a team of scientists including Anna Blumental-Perry, PhD, from the department of surgery, and Xing-Huang Gao, PhD, from the department of genetics and genome sciences, at Case Western Reserve University School of Medicine embarked on a study to examine COPD development at the cellular level. Specifically, Blumental-Perry and her team sought to better understand the mechanisms of a relatively new scientific concept – the smoke induced collapse of protein homeostasis and its contribution to age-dependent onset of COPD. Knowing that upon inhalation of cigarette smoke (CS), the free radicals in it can reach the interior of lung cells where they react with a wide variety of cell proteins and affect their functions, the scientists formed the hypothesis that CS-free radicals can interfere with proper folding of the proteins within the cell.

The scientists’ findings, recently published in The Journal of Biological Chemistry, demonstrated that free radicals—small, unstable molecules present in CS—can reach the endoplasmic reticulum, a cellular organelle that is critical in manufacturing and transporting fats, steroids, hormones and various proteins, and alter its function by oxidizing and damaging its most abundant and crucial to protein folding chaperone, Protein Disulfide Isomerase (PDI).

Determining that PDI is a critical factor in the development of COPD, the researchers identified for the first time how cells adapt to the presence of less functional PDI, which is by increasing the levels of it through a novel mechanism at the protein synthesis level, as opposed to the level of gene transcription. Since adaptation wears off with age, the researchers have now identified one of the first clues to age-dependency in COPD onset.

“Understanding the mechanisms of the collapse of protein homeostasis in COPD allows us to focus on maintaining functional levels of PDI. This could improve outcomes for the many patients with COPD as well as potentially giving us clues to improve health with aging.” said Blumental-Perry. “We discovered that PDI is a critical new factor in the pathogenesis of COPD, and that protein collapse in COPD is age dependent and unpredictable. Based on these fascinating findings, we plan to conduct future research targeting failed adaptive systems in an effort to maintain functional levels of PDI, and prevent it from acquisitions of ‘bad’ functions – discoveries that could ultimately help us to identify new therapeutic approaches for COPD.”

This research was supported by Flight Attendants Medical Research Institute Young Clinical Investigator Award 092207; National Institute of Health grants 5P20GM103542 from the National Center for Research Resources; COBRE in Oxidants, Redox Balance and Stress Signaling; CO6 RR015455; R37-DK60596 and R01-DK53307.

For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.