Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E(2) (PGE(2)) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE(2) synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE(2) axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of PGE(2) or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP(2) receptor, which is pivotal for PGE(2) responsiveness. However, cytokine-induced upregulation of PGE(2) biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX-2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE(2) acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE(2) generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma.

A key event in chronic allergic asthma is the TGF-β-induced activation of fibroblasts into α-SMA-positive myofibroblasts which synthesize type-I collagen. In the present study we investigated the effect of the anti-fibrotic molecule BMP-7 in asthma. Balb/c mice were immunized i.p. with ovalbumin in alum and challenged every 2 days with ovalbumin aerosol (two or six challenges for acute and chronic protocols, respectively). The lung was evaluated for: α-SMA and type-I collagen by immunohistochemistry; BMP-7 and TGF- β1 gene expression by qRT-PCR; type-I collagen and Smads 2 and 3 by immunoblotting; mucus by PSA staining. Type-I collagen around bronchi, α-SMA, mucus secretion, TGF- β1 and BMP-7 gene expression were all increased in asthma. The TGF- β1/BMP-7 ratio was higher in the chronic group and correlated with higher levels of collagen. Fibroblasts isolated from asthmatic and healthy lungs produced type-I collagen upon stimulation with TGF- β1 via phosphorylation of Smad-2, Smad-3. Pre-treatment of the fibroblasts with BMP-7 reduced collagen production and Smads phosphorylation. Intranasal treatment of asthmatic mice with recombinant BMP-7 during the immunization protocol reduced lung inflammation and type I collagen deposition. These results suggest a protective role for BMP-7 in lung allergic inflammation, opposing the pro-fibrotic effects of TGF- β1.

Blastocyst reception and implantation require various adaptations of the uterine microenvironment. We have previously shown that in mice, remodeling of the extracellular matrix begins early in pregnancy, characterized by synthesis, degradation and alteration of collagen fibrillogenesis, accompanied by pregnancy stage-dependent expression of glycosaminoglycans and proteoglycans. Fibrillin-1 is a matrix glycoprotein that participates in the formation of elastic fibers and promotes cell adhesion through its integrin-binding domain. In the present study, we used light microscope immunohistochemistry to analyze the distribution of fibrillin-1 in the endometrial stroma of mice during estrous and diestrous, as well as in the pre- and postimplantation periods. Fibrillin-1 was found among endometrial fibroblasts and decidual cells, respectively, in the pre- and postimplantation periods. However, fibrillin-1 organization and distribution in the various regions of the endometrial stroma were found to be pregnancy stage dependent. Fibrillin-1 was also abundant in the basement membrane regions of blood vessels, as well as in the luminal and glandular epithelia. Fibrillin-1 at the maternal-fetal interface and in Reichert’s membrane of embryos at up to 6 days of development might facilitate embryo expansion and fixation. Changes in the fibrillin-1 expression during the peri-implantation period suggest that fibrillin-1 plays a role in preparing the endometrium for embryo implantation.

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Stumm CL. Anti-fibrotic role of PGE 2 and BMP-7 in experimental allergic asthma. [Ph. D. thesis (Immunology)].