Bronchoconstriction: a potential missing link in airway remodelling.
O'Sullivan MJ, Phung TN, Park JA.
Open Biol. 2020 12. 10(12):200254. PMID: 33259745
My research focuses on the role of airway epithelium in the lung. The airway epithelium is the first line of defense against external stimuli. Airway epithelial cells lining on the airway epithelium contribute to homeostasis in the lung, but when they are exposed to excessive biochemical or physical stimuli, the normal defense mechanism turns into the progression of various pathophysiologic conditions. Airway epithelial cells also play important roles in innate and adaptive immunities and inflammation.
Much of the morbidity and mortality associated with persistent asthma is attributable to progressive and irreversible remodeling of the airway wall. Most theories concerning airway remodeling argue that the remodeling process is triggered in response to inflammatory mediators and cytokines.
We hypothesize that airway remodeling is triggered in response to the mechanical stress imposed on the airway epithelium during bronchoconstriction.
We use a compressive in vitro model system (Figure 1). In this system, primary human bronchial epithelial cells are grown in an air-liquid interface (ALI) culture and subjected to compressive stress, which is modeled through the application of a transepithelial pressure gradient at a magnitude of 20 to 30 cm H2O. This magnitude of stress is similar to the magnitude that bronchoconstriction imposes on the airway epithelium, and is significantly higher than the magnitude experienced during normal breathing. The compressive in vitro system recapitulates many aspects of airway remodeling in the absence of inflammatory cells (Putting the Squeeze on Airway Epithelia, Park et al. Physiology. 2015).
The findings using the compressive in vitro system have already led to experiments in humans showing that methacholine-induced bronchoconstriction, in the absence of eosinophilic inflammation, can lead to collagen deposition under the epithelial monolayer, enhanced expression of TGF-*, and increased numbers of goblet cells - key aspects of airway remodeling. These experiments provide in vivo validation of our experimental approach.
A full understanding of the asthmatic response requires many different models; in vitro compressive model system highlights and isolates the effects of mechanical stress on airway epithelial cells. We also use mouse asthma models to verify the physiological effects of target molecules and to identify further mechanisms.
Parker B. Francis Fellowship
Francis Family Foundation
Scientist Development Grant, AHA
American Heart Association
Ann Woolcock Memorial Award (American Thoracic Society)
American Thoracic Society
International Research Visiting Fellowship (The University of Newcastle, Australia)
The University of Newcastle, Australia
O'Sullivan MJ, Phung TN, Park JA.
Open Biol. 2020 12. 10(12):200254. PMID: 33259745
O'Sullivan MJ, Mitchel JA, Mwase C, McGill M, Kanki P, Park JA.
Am J Physiol Lung Cell Mol Physiol. 2021 02 01. 320(2):L246-L253. PMID: 33174447
Hao Y, Bates S, Mou H, Yun JH, Pham B, Liu J, Qiu W, Guo F, Morrow JD, Hersh CP, Benway CJ, Gong L, Zhang Y, Rosas IO, Cho MH, Park JA, Castaldi PJ, Du F, Zhou X.
Am J Respir Crit Care Med. 2020 11 01. 202(9):1225-1236. PMID: 32551799
Mitchel JA, Das A, O'Sullivan MJ, Stancil IT, DeCamp SJ, Koehler S, Ocaña OH, Butler JP, Fredberg JJ, Nieto MA, Bi D, Park JA.
Nat Commun. 2020 10 07. 11(1):5053. PMID: 33028821
Veerati PC, Mitchel JA, Reid AT, Knight DA, Bartlett NW, Park JA, Grainge CL.
Eur Respir Rev. 2020 Sep 30. 29(157). PMID: 32759373
Hou M, Han J, Li G, Kwon MY, Jiang J, Emani S, Taglauer ES, Park JA, Choi EB, Vodnala M, Fong YW, Emani SM, Rosas IO, Perrella MA, Liu X.
Stem Cell Res Ther. 2020 02 13. 11(1):55. PMID: 32054514
O'Sullivan MJ, Mitchel JA, Das A, Koehler S, Levine H, Bi D, Nagel ZD, Park JA.
Front Cell Dev Biol. 2020. 8:21. PMID: 32117962
Kiliç A, Ameli A, Park JA, Kho AT, Tantisira K, Santolini M, Cheng F, Mitchel JA, McGill M, O'Sullivan MJ, De Marzio M, Sharma A, Randell SH, Drazen JM, Fredberg JJ, Weiss ST.
Sci Rep. 2020 01 22. 10(1):966. PMID: 31969610
Kim JH, Pegoraro AF, Das A, Koehler SA, Ujwary SA, Lan B, Mitchel JA, Atia L, He S, Wang K, Bi D, Zaman MH, Park JA, Butler JP, Lee KH, Starr JR, Fredberg JJ.
Biochem Biophys Res Commun. 2020 01 15. 521(3):706-715. PMID: 31699371
Kim SH, Mitchel JA, McGill M, Cremona TP, Baek JW, Kasahara DI, Anathy V, Israel E, Park JA.
J Allergy Clin Immunol. 2019 10. 144(4):1116-1118.e4. PMID: 31228474
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