Pabelick, Christina M.

This novel study deciphered the expression and function of protein phosphatase 2Aα (PP2Aα) in airway smooth muscle (ASM) during asthma and/or inflammation. We showed robust expression of PP2Aα in human ASM while its downregulation in asthmatic ASM. Similarly, we demonstrated reduced PP2Aα expression in ASM exposed to proinflammatory cytokines. PP2Aα activation inhibited bronchoconstriction of isolated mouse bronchi. In addition, we unveiled that PP2Aα activation inhibits the intracellular calcium release and myosin light chain phosphorylation in human ASM.

Abstract Airway remodeling is a cardinal feature of asthma, associated with increased airway smooth muscle (ASM) cell mass and upregulation of extracellular matrix deposition. Exaggerated ASM cell migration contributes to excessive ASM mass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 in mitogen (PDGF [platelet-derived growth factor])-induced human ASM cell proliferation in vitro and airway remodeling in vivo in a mouse model of asthma. Here, we examined the mechanisms by which KISS1R activation regulates mitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASM cell migration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activation modulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASM cells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling.

With continued smoking of tobacco products and expanded use of nicotine delivery devices worldwide, understanding the impact of smoking and vaping on respiratory health remains a major global unmet need. Although multiple studies have shown a strong association between smoking and asthma, there is a relative paucity of mechanistic understanding of how elements in cigarette smoke impact the airway. Recognizing that nicotine is a major component in both smoking and vaping products, it is critical to understand the mechanisms by which nicotine impacts airways and promotes lung diseases such as asthma. There is now increasing evidence that α7 nicotinic acetylcholine receptors (α7nAChRs) are critical players in nicotine effects on airways, but the mechanisms by which α7nAChR influences different airway cell types have not been widely explored. In this review, we highlight and integrate the current state of knowledge regarding nicotine and α7nAChR in the context of asthma and identify potential approaches to alleviate the impact of smoking and vaping on the lungs.

Introduction Asthma is acutely aggravated and chronically worsened by cigarette smoke (CS), as well as secondhand smoke exposure. In this regard, studies show significant differences between women vs. men in their response to the detrimental effects of CS, suggesting that female sex steroids (particularly estrogen) may be involved. Airway smooth muscle (ASM) cell proliferation and airway remodeling is a key feature of asthma and COPD. Surprisingly, there is little information regarding sex steroid effects on cigarette smoke‐induced changes of airway structure and function. In the current study, we hypothesize that estrogen interferes with CSE exposure‐induced proliferation, thereby contributing to airway smooth muscle remodeling. Methods and Results Human ASM tissues (epithelium‐denuded) and isolated ASM cells were from lung samples of patients with known smoking histories undergoing thoracic surgery for non‐infectious, focal pathology. Exposure of human ASM to cigarette smoke extract (CSE, Kentucky research cigarette 1RF4) 1%CSE or 2%CSE for 24h significantly increased ASM proliferation (proliferation assay: Cell Titer Aueous One, and Cyquant). Exposure of physiological concentrations of 17‐β‐estradiol (E 2, 1nM) did not alter ASM proliferation at baseline. Interestingly, E 2 pre‐treatment (1 h prior to CSE exposure) significantly reduced CSE‐induced human ASM proliferation. This was further confirmed by Western blot analysis for proliferative markers PCNA and Cyclin E. In addition, to explore the mechanistic bases of differential effects of E 2 on ASM proliferation under basal and CSE‐exposed conditions, the estrogen receptor profile in ASM tissue was screened in parallel for patients with and without smoking histories. Human ASM tissue from smokers samples showed substantial increased ERα and β expression compared to non‐smokers. Inhibition of ERα and β prevented the effects of estrogen on CSE‐induced increases in proliferation. Conclusions Collectively, estrogen exposure decreased human ASM proliferation induced by CSE. ER expression and signaling is enhanced in CSE induced inflamed ASM, with a potential beneficial role in reducing remodeling with CS exposure. These results will lay the foundation for examining the role of estrogen signaling in pathogenesis of cigarette smoke‐induced airway remodeling and possible sex based therapeutic targets in smoking‐related diseases. Support or Funding Information Supported by Flight Attendants Medical Research Institute (VS) and NIH R01 grant HL123494 (VS)