What is the real culprit of smoking-induced COPD?

Cigarette smoking poses a health hazard for people. Some kind of substance induced by cigarette smoking in merely several minutes may well activate T cells to induce an adaptive immune response. Long exposure to cigarette smoking may ultimately result in the incidence of chronic obstructive pulmonary disease (COPD).

At present, the health of lungs has riveted increasing attention among the general public, particularly among those cigarette smokers. As a matter of fact, habitual cigarette smoking constitutes a major risk factor for COPD which has become a global public health issue. One study in 2018 reveals that there were about 100 million COPD patients in China, accounting for 25% of the total number of COPD patients in the world. It also indicates that the overall prevalence of spirometry-defined COPD was 8.6%. Prevalence among those aged 40 years or older amounted to 13.7% while that among those aged 60 years or older reached 27%.

In recent years, the research team led by Prof. SHEN Huahao and Prof. CHEN Zhihua in the Department of Respiratory and Critical Care Medicine at the Second Affiliated Hospital discovered and proved the pathogenic mechanism for COPD through basic and clinical research. Their research findings are published in the European Respiratory Journal.  

“Why does cigarette smoking contribute to COPD? Why do some people come down with COPD even after they quit smoking?”

CHEN Zhihua has been long bewildered by these two key questions. In the recent decade, the research team led by SHEN Huahao and CHEN Zhihua has been committed to figuring out the answers to these questions. On the strength of their previous work, CHEN Zhihua believed that the autoimmune process may be involved in the development of COPD.

To address this question, mice were exposed to cigarette smoke for 2 weeks and challenged intratracheally with elastin for 3 days or 1 month. In this way, they could be used to emulate the similar symptoms and pathologic characteristics of COPD patients. These animal experiments attested to the critical role of elastin which may well be the real culprit of COPD.

Interestingly enough, those mice which were exposed to cigarette smoke for 2 week would develop airway inflammation related to COPD again when injected elastin even after they returned to normal with fresh air for 6 months (The normal life span for a mouth is 2 years or so, so 6 months is equal to about 20 years for a human being). This indicates that the immune memory caused by brief smoking would become established and that COPD would aggravate when a patient simply quit smoking without taking any other intervention measure.

“The pathogenic mechanism for COPD remains elusive. At present, relevant drugs for COPD can relieve symptoms, but they cannot be an effective cure pathogenically,” said SHEN Huahao, “Only if the culprit is tracked down will the problem be essentially solved.”

Elastin is not born malicious; rather it is one of the key components of our lungs, responsible for the elasticity of lungs. Without the elasticity of our lungs, we will have difficulty breathing. Then how does it become the number-one culprit?

Researchers discovered that it is not elastin but elastin peptides that result in COPD. They observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodeling, lung function decline, and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adaptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, CS exposure induced elastin-specific T cell responses were MMP12-dependent, while the ensuing immune inflammatory processes were IL17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.

These data demonstrated that MMP12-generated elastin fragments serve as a self-antigen and drive the CS-induced autoimmune process in mice that results in a bronchitis-like phenotype and airspace enlargement.

Another significant contribution of this research lies in the establishment of a novel mouse model. Not only is this model able to mimic most human COPD characteristics, but it is also highly convenient and repeatable.  

“I hope that our new model will tremendously promote basic research into COPD. Meanwhile, we believe that MMP12, active elastin peptides, or IL17A could serve as novel therapeutic targets for COPD,” said SHEN Huahao.