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New clues to COPD linked to proteostasis imbalance caused by cigarette smoke

Date:
June 22, 2016
Source:
Case Western Reserve University
Summary:
Free radicals 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).
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Oxidized protein disulfide isomerase (PDI) from the lung of mice that smoke one cigarette at 12, 24 and 48 hours after smoking, revealing how long damage can be detected.
Credit: Case Western Reserve University School of Medicine

Few threats to public health are as perilous as cigarette smoking, with more than 435,000 Americans dying each year of tobacco-related pulmonary illnesses such as chronic obstructive pulmonary disease (COPD). COPD ranks as the third-leading cause of tobacco-related morbidity and mortality worldwide in 2012 and the global cost of illness related to COPD is expected to rise to $4.8 trillion by 2030, yet there are currently no effective medical treatments to cure COPD or stop its progression.

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."


Story Source:

Materials provided by Case Western Reserve University. Note: Content may be edited for style and length.


Journal Reference:

  1. Harshavardhan Kenche, Zhi-Wei Ye, Kokilavani Vedagiri, Dylan M. Richards, Xing-Huang Gao, Kenneth D. Tew, Danyelle M. Townsend, Anna Blumental-Perry. Adverse Outcomes Associated with Cigarette Smoke Radicals Related to Damage to Protein-disulfide Isomerase. Journal of Biological Chemistry, 2016; 291 (9): 4763 DOI: 10.1074/jbc.M115.712331

Cite This Page:

Case Western Reserve University. "New clues to COPD linked to proteostasis imbalance caused by cigarette smoke." ScienceDaily. ScienceDaily, 22 June 2016. <www.sciencedaily.com/releases/2016/06/160622115125.htm>.
Case Western Reserve University. (2016, June 22). New clues to COPD linked to proteostasis imbalance caused by cigarette smoke. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2016/06/160622115125.htm
Case Western Reserve University. "New clues to COPD linked to proteostasis imbalance caused by cigarette smoke." ScienceDaily. www.sciencedaily.com/releases/2016/06/160622115125.htm (accessed May 23, 2017).

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