Asthmatic Epithelial Cell Proliferation and Stimulation of Collagen Production

Abstract

Epithelial injury and subepithelial collagen deposition are characteristic of asthma. We hypothesized that epithelial cell proliferation increases after airway injury in asthmatics, that epithelial cells stimulate lung myofibroblast collagen production, and that both processes are modulated by allergen-recruited inflammatory cells. Epithelial cells obtained at baseline, 1 d, and 1 and 2 wk after endobronchial allergen challenge from asthmatics and nonasthmatics were placed in culture, with and without bronchoalveolar lavage cells obtained from the same segment. Epithelial cell proliferation and collagen synthesis by human lung myofibroblasts stimulated with culture medium from these epithelial cells were determined. Epithelial proliferation increased (108 +/- 50% above baseline, p = 0.01 for d, and p = 0.004 for group x day interaction) 1 wk postchallenge in cells from asthmatics, but not from nonasthmatics, and required bronchoalveolar lavage cell coculture. Culture medium from epithelium harvested from asthmatics, but not from nonasthmatics, at 1 to 2 wk postchallenge stimulated collagen type III production 50% to 70% (p = 0.043 for clinical group, p = 0.012 for day, and p = 0.022 for group x day interaction), but not collagen type I. This effect was independent of an acute eosinophilic response. We conclude that epithelial cells from asthmatics, but not from nonasthmatics, are stimulated to proliferate after allergen challenge, and over 1 to 2 wk postchallenge, stimulate collagen type III synthesis by lung myofibroblasts. Epithelial cell proliferation appears dependent upon infiltrating inflammatory cells, but stimulation of collagen type III does not.

Klebsiella pneumoniae MrkD-mediated biofilm formation on extracellular matrix- and collagen-coated surfaces

“…The non-adhesive strains were not able to grow on the slides under these conditions. Although we did not directly demonstrate that the MrkD protein interacts with any specific type of collagen in the ECM of the HBE cells, it is known that collagen is an integral component of the matrix synthesized by cells in vitro (Fenwick et al, 2001;Hastie et al, 2002;Yurchenko & O'Rear, 1994). However, the composition of the ECM produced by the HBE cells has not been investigated in detail.…”

Extracellular Matrix, Integrins, and Mesenchymal Cell Function in the Airways

“…Pro-collagen 1 expression in response to Interleukin-4 [71] and PDGF [68] is greater in asthmatic fibroblasts than non-asthmatic fibroblasts, although the PDGF response was only observed in severe asthmatics. In contrast, Boulet and co-workers demonstrated that bronchial fibroblasts from asthmatics have the same baseline expression of pro-collagens I and III relative to fibroblasts grown from non-asthmatic patients [72].…”

“…In contrast, the epithelialderived 'true' BM thickness is not altered in asthma. However, it is now accepted that damaged or activated epithelium in asthmatic airways may itself release pro-fibrotic mediators (including granulocyte macrophage colony-stimulating factor (GM-CSF) and TGFβ) which directly stimulate woundtype matrix to be synthesized by myofibroblasts [35,[67][68][69]. Thus, the epithelium is likely to play more than a passive role in the subepithelial ECM deposition.…”

Migration of Airway Smooth Muscle Cells

“…The ultrastructural similarity of these myofibroblasts to smooth muscle cells and the location and apparent motility of the cells are consistent with some or all of the myofibroblasts being derived from smooth muscle cells that actively migrated into the lamina reticularis. This migration process could be significant for the pathogenesis of asthma, because evidence suggests that myofibroblasts secrete the collagen matrix that thickens the lamina reticularis, participate in epithelial cell-mesenchymal interactions, modulate eosinophil survival, and participate in the remodeling of smooth muscle bundles during muscle hyperplasia (11)(12)(13)(14)(15). Therefore, it is possible that the active migration of ASMCs, or cells closely derived from them, is central to certain aspects of airway remodeling, and, ultimately, a useful therapeutic target in asthma.…”