Eosinophil-derived TGF-β has been implicated in remodeling events in asthma. We hypothesized that reduction of bronchial mucosal eosinophils with anti-IL-5 would reduce markers of airway remodeling. Bronchial biopsies were obtained before and after three infusions of a humanized, anti-IL-5 monoclonal antibody (mepolizumab) in 24 atopic asthmatics in a randomized, double-blind, placebo-controlled study. The thickness and density of tenascin, lumican, and procollagen III in the reticular basement membrane (RBM) were quantified immunohistochemically by confocal microscopy. Expression of TGF-β1 mRNA by airway eosinophils was assessed by in situ hybridization, and TGF-β1 protein was measured in bronchoalveolar lavage (BAL) fluid by ELISA. At baseline, airway eosinophil infiltration and ECM protein deposition was increased in the RBM of asthmatics compared with nonasthmatic controls. Treating asthmatics with anti-IL-5 antibody, which specifically decreased airway eosinophil numbers, significantly reduced the expression of tenascin, lumican, and procollagen III in the bronchial mucosal RBM when compared with placebo. In addition, anti-IL-5 treatment was associated with a significant reduction in the numbers and percentage of airway eosinophils expressing mRNA for TGF-β1 and the concentration of TGF-β1 in BAL fluid. Therefore eosinophils may contribute to tissue remodeling processes in asthma by regulating the deposition of ECM proteins.

/pdf/anti-il-5-treatment-reduces-deposition-of-ecm-proteins-in-1lfxiw4q9r.pdf

Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics

Pulmonary fibrosis: pathogenesis, etiology and regulation

Asthma is estimated to affect 15 million people in the United States. After declining in the 1970s, its prevalence, morbidity, and mortality have increased since the 1980s. It now affects 1 in 7 children in the United Kingdom, and is the most frequent reason for preventable childhood hospitalizations in the United States. In 1990, total asthma-related health care costs were estimated at 6.2 billion dollars in the United States. This figure exceeded 10 billion dollars by 1995.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.161.supplement_2.a1q4-4

Airway remodeling in asthma.

The mechanisms contributing to airway wall remodeling in asthma are under investigation to identify appropriate therapeutic targets. Bronchial myofibroblasts would represent an important target because they play a crucial role in the genesis of subepithelial fibrosis, a characteristic feature of the remodeling process, but their origin is poorly understood. We hypothesized that they originate from fibrocytes, circulating cells with the unique characteristic of expressing the hemopoietic stem cell Ag CD34 and collagen I. In this study we show that allergen exposure induces the accumulation of fibrocyte-like cells in the bronchial mucosa of patients with allergic asthma. These cells are CD34-positive; express collagen I and α-smooth muscle actin, a marker of myofibroblasts; and localize to areas of collagen deposition below the epithelium. By tracking labeled circulating fibrocytes in a mouse model of allergic asthma, we provide evidence that fibrocytes are indeed recruited into the bronchial tissue following allergen exposure and differentiate into myofibroblasts. We also show that human circulating fibrocytes acquire the myofibroblast phenotype under in vitro stimulation with fibrogenic cytokines that are produced in exaggerated quantities in asthmatic airways. These results indicate that circulating fibrocytes may function as myofibroblast precursors and may contribute to the genesis of subepithelial fibrosis in asthma.

/pdf/identification-of-circulating-fibrocytes-as-precursors-of-3pzihzmqil.pdf

Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma

Matrix metalloproteinase (MMP)-9 (Gelatinase B, 92-kD type IV collagenase, EC 3.4.24.35) is an MMP that is present in low quantities in the healthy adult lung, but much more abundant in several lung diseases, including asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). Despite numerous reports of MMP-9 in these and other lung diseases, whether MMP-9 is causal in lung remodeling or part of the inflammatory and reparative response remains to be determined. Many intrinsic lung cells can be stimulated to produce MMP-9, but much of the information regarding MMP-9 in the lung deals with MMP-9 from inflammatory cells. The multiple locations and cell types producing MMP-9 are consistent with multiple functions in different microenvironments. In addition to digestion of structural proteins and antiproteases, MMP-9 can modify cellular function by regulation of cytokines and matrix-bound growth factors. Determining the role of MMP-9 in health and disease will be important,...

https://www.atsjournals.org/doi/pdf/10.1165/rcmb.2002-0166TR

Matrix metalloproteinase-9 in lung remodeling.

In order to investigate the effect of boron on the precipitation behavior of β phase in Al-Mn-Mg-B alloy used as a material for cask baskets, 1.00×104 hours aging treatment was carried out focusing on the temperature history in the cask as in the previous report, and the Time-temperature-precipitation diagram and Supersaturation-diffusion length-precipitation diagram were evaluated using the change tendency of the specific resistance obtained. In the Al-Mn-Mg-B alloy, although grain refinement by AlB2 was confirmed, the effect of boron addition on the precipitation rate of β phase was hardly recognized. That is to say, it was confirmed that the grain boundary and the interface between B compound and matrix phase hardly contributed as nucleation sites of β phase. In conclusion, it is considered that the reduction of the solid solution Mg content in the Al-Mn-Mg-B alloy does not occur even after 60 years if the Mg content is 1.0 mass% as in the Al-Mn-Mg alloy. 

Effect of B addition on precipitation behavior of β phase in Al-Mn-Mg-B alloys

Background: Bronchial asthma is characterized by airway structural changes, including mucosal inflammation and subepithelial collagen deposition. An imbalance between the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is thought to play a critical role in the synthesis or degradation of the extracellular matrix of the airway architecture. However, the relationship between subepithelial basement membrane thickness and these enzymes in asthma has not been determined. Objective: We compared the thickness of collagen and tenascin deposition and the expression of MMP-9 and TIMP-1 in bronchial biopsy specimens from subjects with asthma and control subjects. Methods: Bronchial biopsy specimens were obtained from 25 subjects with asthma and 10 healthy control subjects to estimate the extent of collagen and tenascin deposition in subepithelial reticular basement membrane by immunohistochemical staining. Using a computer-assisted image analysis system, we quantitated expression of both epithelial and submucosal MMP-9 and TIMP-1. The numbers of inflammatory cells were also determined. Results: Subjects with asthma exhibited greater thickness of collagen III ( P P P P P s = 0.70, P s = 0.67, P s = 0.58, P s = 0.43, P s = 0.69, P 1 (type III collagen, r s = –0.89, P s = –0.90, P s = –0.88, P s = –0.59, P s = –0.47, P s = –0.48, P Conclusion: These findings suggest that collagen III, collagen V, and tenascin deposition in basement membrane in subjects with bronchial asthma are associated with increased expression of MMP-9, which may be produced by eosinophils, and that airway remodeling in subjects with asthma may be related to air-flow obstruction and airway hyperresponsiveness. (J Allergy Clin Immunol 1998;102:783-8.)

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

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Effect of B addition on precipitation behavior of β phase in Al-Mn-Mg-B alloys

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