Role of Neuro‐immune Interactions in a Cigarette Smoke‐induced Chronic Airway Inflammation Mouse Model

Abstract

Chronic obstructive pulmonary disease characterized by progressive persistent airway inflammation & airway resistance is caused mainly by cigarette smoke‐triggered inflammatory cascades & tissue damage. The airways are densely innervated by capsaicin‐sensitive sensory nerves expressing Transient Receptor Potential Vanilloid 1 (TRPV1) ion channels, which play an important regulatory role in inflammation through the release of sensory neuropeptides. Pro‐inflammatory peptides, such as tachykinins (substance P, neurokinin A) encoded by the TAC1 gene induce neurogenic inflammation via NK1 & NK2 receptor activation in the innervated area. The overall significance of these mediators depends on the pathophysiological mechanisms involved in certain inflammatory processes. Therefore, we established a predictive mouse model of cigarette smoke‐induced chronic bronchitis & consequent airway hyperresponsiveness to investigate the roles of TRPV1 channel & tachikinins.We exposed TRPV1−/− & TAC1−/− gene‐deleted mice and their C57Bl/6 wildtype counterparts to cigarette smoke in a whole body smoke exposure chamber for 3 months. Bronchial responsiveness & enhanced pause (Penh) correlating with airway resistance to inhalation of 22 mM carbachol were measured with unrestrained whole body plethysmography weekly. At the end of each month inflammatory cell profile and count from the bronchoalveolar lavage fluid (BALF), semiquantitative histopathological scoring of the lung, myeloperoxidase (MPO) activity with spectrophotometry & IL‐1β concentrations with ELISA were performed.In wildtype mice mild bronchial hyperresponsiveness developed in the 1st month, then it decreased & started to increase after 10 weeks. The inflammatory cell peak in BALF was observed in the 2nd month, correlating with the histology. In the 1st month significant perivascular/peribronchial edema, in the 2nd month remarkable inflammatory cell accumulation, then increasing atelectasy, emphysema, mucus production & irregular bronchiolar mucosa were observed. Lung IL‐1β concentration gradually increased, but MPO activity only transiently elevated in the 2nd month. Hyperreactivity occured earlier & increased significantly in TRPV1−/−, but did not change in TAC1−/− mice. Remarkably more severe inflammatory histopathological parameters, higher BALF cell counts, MPO activity a& IL‐1β production were observed in TRPV1‐deficient mice. Meanwhile, some inflammatory alterations in the 1st month, & BALF cell counts in the 2nd month were significantly decreased in the TAC1 gene‐deleted mice.Neurogenic inflammatory mechanisms are not crucial in chronic cigarette smoke‐induced inflammation & hyperresponsiveness. The overall role of TRPV1 receptor is protective in smoking‐induced chronic bronchitis.Support or Funding InformationÚNKP‐18‐3 New National Excellence Program of the Ministry of Human CapacitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.