Mechanical compression attenuates normal human bronchial epithelial wound healing
Stephen P Arold, Nikita Malavia, Steven C George, Stephen P Arold, Nikita Malavia, Steven C George
Abstract
Background: Airway narrowing associated with chronic asthma results in the transmission of injurious compressive forces to the bronchial epithelium and promotes the release of pro-inflammatory mediators and the denudation of the bronchial epithelium. While the individual effects of compression or denudation are well characterized, there is no data to elucidate how these cells respond to the application of mechanical compression in the presence of a compromised epithelial layer.
Methods: Accordingly, differentiated normal human bronchial epithelial cells were exposed to one of four conditions: 1) unperturbed control cells, 2) single scrape wound only, 3) static compression (6 hours of 30 cmH2O), and 4) 6 hours of static compression after a scrape wound. Following treatment, wound closure rate was recorded, media was assayed for mediator content and the cytoskeletal network was fluorescently labeled.
Results: We found that mechanical compression and scrape injury increase TGF-beta2 and endothelin-1 secretion, while EGF content in the media is attenuated with both injury modes. The application of compression after a pre-existing scrape wound augmented these observations, and also decreased PGE2 media content. Compression stimulated depolymerization of the actin cytoskeleton and significantly attenuated wound healing. Closure rate was partially restored with the addition of exogenous PGE2, but not EGF.
Conclusion: Our results suggest that mechanical compression reduces the capacity of the bronchial epithelium to close wounds, and is, in part, mediated by PGE2 and a compromised cytoskeleton.
Figures
References
- Cohn L, Elias JA, Chupp GL. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol. 2004;22:789–815.
- Howarth PH, Wilson J, Djukanovic R, Wilson S, Britten K, Walls A, Roche WR, Holgate ST. Airway inflammation and atopic asthma: a comparative bronchoscopic investigation. Int Arch Allergy Appl Immunol. 1991;94(1–4):266–269.
- Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Invest. 1999;104(8):1001–1006.
- Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S. Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol. 1998;102(5):783–788.
- Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet. 1989;1(8637):520–524.
- Boulet L, Belanger M, Carrier G. Airway responsiveness and bronchial-wall thickness in asthma with or without fixed airflow obstruction. Am J Respir Crit Care Med. 1995;152(3):865–871.
- Laursen LC, Taudorf E, Borgeskov S, Kobayasi T, Jensen H, Weeke B. Fiberoptic bronchoscopy and bronchial mucosal biopsies in asthmatics undergoing long-term high-dose budesonide aerosol treatment. Allergy. 1988;43(4):284–288.
- Tohda Y, Kubo H, Ito M, Fukuoka M, Nakajima S. Histopathology of the airway epithelium in an experimental dual-phase model of bronchial asthma. Clin Exp Allergy. 2001;31(1):135–143.
- Arm JP, Lee TH. The pathobiology of bronchial asthma. Adv Immunol. 1992;51:323–382.
- Carter PM, Heinly TL, Yates SW, Lieberman PL. Asthma: the irreversible airways disease. J Investig Allergol Clin Immunol. 1997;7(6):566–571.
- Gunst SJ, Warner DO, Wilson TA, Hyatt RE. Parenchymal interdependence and airway response to methacholine in excised dog lobes. J Appl Physiol. 1988;65(6):2490–2497.
- Wiggs BR, Hrousis CA, Drazen JM, Kamm RD. On the mechanism of mucosal folding in normal and asthmatic airways. J Appl Physiol. 1997;83(6):1814–1821.
- Tschumperlin DJ, Shively JD, Kikuchi T, Drazen JM. Mechanical stress triggers selective release of fibrotic mediators from bronchial epithelium. Am J Respir Cell Mol Biol. 2003;28(2):142–149.
- Tschumperlin DJ, Shively JD, Swartz MA, Silverman ES, Haley KJ, Raab G, Drazen JM. Bronchial epithelial compression regulates MAP kinase signaling and HB-EGF-like growth factor expression. Am J Physiol Lung Cell Mol Physiol. 2002;282(5):L904–911.
- Tschumperlin DJ, Drazen JM. Mechanical stimuli to airway remodeling. Am J Respir Crit Care Med. 2001;164(10 Pt 2):S90–94.
- Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000;161(5):1720–1745.
- Gray TE, Guzman K, Davis CW, Abdullah LH, Nettesheim P. Mucociliary differentiation of serially passaged normal human tracheobronchial epithelial cells. Am J Respir Cell Mol Biol. 1996;14(1):104–112.
- Swartz MA, Tschumperlin DJ, Kamm RD, Drazen JM. Mechanical stress is communicated between different cell types to elicit matrix remodeling. Proc Natl Acad Sci USA. 2001;98(11):6180–6185.
- Randell SH, Walstad L, Schwab UE, Grubb BR, Yankaskas JR. Isolation and culture of airway epithelial cells from chronically infected human lungs. In Vitro Cell Dev Biol Anim. 2001;37(8):480–489.
- Savla U, Appel HJ, Sporn PH, Waters CM. Prostaglandin E(2) regulates wound closure in airway epithelium. Am J Physiol Lung Cell Mol Physiol. 2001;280(3):L421–431.
- Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J, Welsh MJ. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature. 2003;422(6929):322–326.
- Thompson HG, Mih JD, Krasieva TB, Tromberg BJ, George SC. Epithelial-derived TGF-beta2 modulates basal and wound-healing subepithelial matrix homeostasis. Am J Physiol Lung Cell Mol Physiol. 2006;291(6):L1277–1285.
- Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, Davies DE. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. Faseb J. 2000;14(10):1362–1374.
- Hamilton LM, Torres-Lozano C, Puddicombe SM, Richter A, Kimber I, Dearman RJ, Vrugt B, Aalbers R, Holgate ST, Djukanovic R, et al. The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma. Clin Exp Allergy. 2003;33(2):233–240.
- Savla U, Waters CM. Mechanical strain inhibits repair of airway epithelium in vitro. Am J Physiol. 1998;274(6 Pt 1):L883–892.
- Savla U, Olson LE, Waters CM. Mathematical modeling of airway epithelial wound closure during cyclic mechanical strain. J Appl Physiol. 2004;96(2):566–574.
- Savla U, Sporn PH, Waters CM. Cyclic stretch of airway epithelium inhibits prostanoid synthesis. Am J Physiol. 1997;273(5 Pt 1):L1013–1019.
- Wilson SE, Liang Q, Kim WJ. Lacrimal gland HGF, KGF, and EGF mRNA levels increase after corneal epithelial wounding. Invest Ophthalmol Vis Sci. 1999;40(10):2185–2190.
- Lotz MM, Rabinovitz I, Mercurio AM. Intestinal restitution: progression of actin cytoskeleton rearrangements and integrin function in a model of epithelial wound healing. Am J Pathol. 2000;156(3):985–996.
- Waters CM, Savla U. Keratinocyte growth factor accelerates wound closure in airway epithelium during cyclic mechanical strain. J Cell Physiol. 1999;181(3):424–432.
- Sawyer SJ, Norvell SM, Ponik SM, Pavalko FM. Regulation of PGE(2) and PGI(2) release from human umbilical vein endothelial cells by actin cytoskeleton. Am J Physiol Cell Physiol. 2001;281(3):C1038–1045.
Source: PubMed