Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation☆☆☆★★★

Hoshino, Makoto; Nakamura, Yutaka; Sim, JaeJoon; Shimojo, Jun; Isogai, Sho

doi:10.1016/s0091-6749(98)70018-1

Cited by 266 publications

(222 citation statements)

References 29 publications

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“…This effect was magnitude-dependent. Furthermore, collagen type III was the most markedly increased of the three types investigated (I, III, and V), which is consistent with asthmaassociated airway wall thickening (5,(13)(14)(15). In fact, the entire integrated response-collagen synthesis, increased HBEC production of fibronectin, and increased MMP-9͞TIMP-1 ratiomimics many facets of the fibrotic response observed in patients with asthma, yet in the absence of inflammatory cells.…”

Section: Discussionsupporting

confidence: 74%

See 1 more Smart Citation

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Swartz

Tschumperlin

Kamm

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

241

158

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Tissue remodeling often reflects alterations in local mechanical conditions and manifests as an integrated response among the different cell types that share, and thus cooperatively manage, an extracellular matrix. Here we examine how two different cell types, one that undergoes the stress and the other that primarily remodels the matrix, might communicate a mechanical stress by using airway cells as a representative in vitro system. Normal stress is imposed on bronchial epithelial cells in the presence of unstimulated lung fibroblasts. We show that (i) mechanical stress can be communicated from stressed to unstressed cells to elicit a remodeling response, and (ii) the integrated response of two cell types to mechanical stress mimics key features of airway remodeling seen in asthma: namely, an increase in production of fibronectin, collagen types III and V, and matrix metalloproteinase type 9 (MMP-9) (relative to tissue inhibitor of metalloproteinase-1, TIMP-1). These observations provide a paradigm to use in understanding the management of mechanical forces on the tissue level.airway wall remodeling ͉ airway epithelium ͉ asthma ͉ lung fibroblasts I n the past two decades, it has been well established that many cells are sensitive to mechanical forces and can change their phenotype and surrounding extracellular matrix (ECM) in response to changes in their mechanical environment. However, it has not been established how mechanical forces are managed on a tissue level, in which different cell types share a common ECM and may alter their mechanical environment by inducing other cells to remodel the ECM.The airway wall is an example of a mechanically active tissue (e.g., bronchoconstriction) composed of multiple cell types that share a common extracellular matrix. It is known that patients with poorly controlled asthma develop structural changes in the airway wall: the subepithelial layers significantly thicken (1-4) and there is deposition of collagen types III and V, among other fibrous proteins, beneath the basement membrane (4, 5). The major consequences of airway remodeling are altered tissue mechanics and airway hyperresponsiveness (6).The remodeling process in asthma has been attributed to the effects of the inflammatory response that characterizes the disease, but this sequence of events has only been inferentially established. We propose an alternative hypothesis for airway wall remodeling in asthma, namely that the mechanical stress associated with bronchoconstriction that is imposed on bronchial epithelial cells could, itself, stimulate and amplify airway wall remodeling in the absence of inflammatory agents. Specifically, we hypothesize that, when airway epithelial cells are subjected to mechanical stress, they act in concert with subepithelial fibroblasts to modulate the fibrous structure of the airway in response to this mechanical stress.This hypothesis, if true, would provide two key insights. First, it would challenge the idea that airway wall remodeling in asthma is solely the consequence of inflam...

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Section: Discussionsupporting

confidence: 74%

“…These included collagen types I, III, and V, which are the primary types produced during asthma-related airway wall remodeling (5,(13)(14)(15), particularly type III. We also examined the presence of matrix metalloproteinase-9 (MMP-9) along with its inhibitor, tissue inhibitor of metalloproteinase-1…”

mentioning

confidence: 99%

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Swartz

Tschumperlin

Kamm

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

241

158

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show abstract

“…Not surprisingly, then, the collagens up-regulated following egg exposure include types I, III, V, and XVIII, but not type IV. Interestingly, the subepithelial fibrosis manifested in asthma consists of collagens III and V, while the basal lamina, consisting of type IV, remains unchanged (43,44). Also, the ratio of collagens to each other is important.…”

Section: Discussionmentioning

confidence: 99%

Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair

Sandler

Mentink‐Kane

Cheever

et al. 2003

The Journal of Immunology

228

203

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T helper 1 responses are typically proinflammatory, while Th2 responses have been considered regulatory. Interestingly, Th2 responses characterize a number of pulmonary diseases, many of which terminate in tissue remodeling and fibrosis. We developed a mouse model using Schistosoma mansoni eggs and cytokine-deficient mice to induce highly polarized Th1- or Th2-type inflammation in the lung. In this study, we examined the pathology and cytokine profiles in Th1- and Th2-polarized environments and used oligonucleotide microarray analysis to decipher the genes responsible for these effects. We further elaborated on the results using IL-10- and IL-13-deficient mice because these cytokines are believed to be the central regulators of Th2-associated pathology. We found that the Th1-polarized mice developed small granulomas with less fibrosis while expressing genes characteristic of tissue damage. Th2-polarized mice, in contrast, formed large granulomas with massive collagen deposition and up-regulated genes associated with wound healing, specifically, arginase, collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of MMP. In addition, several members of the chitinase-like family were up-regulated in the lung following egg challenge. We also developed a method of defining the net collagen deposition using the expression profiles of several collagen, MMP, and tissue inhibitors of MMP genes. We found that Th1-polarized mice did not elaborate collagens or MMPs and therefore did not have a significant capacity for repair in this model. Thus, Th1-mediated inflammation is characterized by tissue damage, while Th2 directs wound healing and fibrosis.

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“…Human studies reveal an association between severity of remodeling and AHR in asthma (Chetta et al, 1996;Hoshino et al, 1998), as well as a correlation between increasing subepithelial fibrosis and progression from asymptomatic AHR to asthma (Laprise et al, 1999). However, our previous studies using this experimental model suggest that remodeling and development of AHR can be uncoupled in IL-5-deficient animals, which develop significant airway wall remodeling but not AHR , as well as in IL-13-deficient animals, which do not exhibit remodeling but continue to be hyperreactive to methacholine (Kumar et al, 2002a).…”

Section: Foster Et Almentioning

confidence: 99%

“…This is of particular interest because AHR in asthmatics may correlate with the development of changes of remodeling, especially subepithelial fibrosis (Chetta et al, 1996;Hoshino et al, 1998). Increasing subepithelial fibrosis has also been associated with progression from asymptomatic AHR to asthma (Laprise et al, 1999).…”

mentioning

confidence: 99%

CD4+ T-Lymphocytes Regulate Airway Remodeling and Hyper-Reactivity in a Mouse Model of Chronic Asthma

Foster

Yang

Herbert

et al. 2002

Laboratory Investigation

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SUMMARY:Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4 ϩ T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4 ϩ T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulinsynthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4 ϩ T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target. (Lab Invest 2002, 82:455-462).

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Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation☆☆☆★★★

Cited by 266 publications

References 29 publications

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair

CD4+ T-Lymphocytes Regulate Airway Remodeling and Hyper-Reactivity in a Mouse Model of Chronic Asthma

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