Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice

Abstract

BACKGROUND AND PURPOSEEndogenous glucocorticoids are pro-resolving mediators, an example of which is the endogenous glucocorticoid-regulated protein annexin A1 (ANXA1). Because silicosis is an occupational lung disease characterized by unabated inflammation and fibrosis, in this study we tested the therapeutic properties of the N-terminal ANXA1-derived peptide annexin 1-(2-26) (Ac2-26) on experimental silicosis. EXPERIMENTAL APPROACHSwiss-Webster mice were administered silica particles intranasally and were subsequently treated with intranasal peptide Ac2-26 (200 μg per mouse) or dexamethasone (25 μg per mouse) for 7 days, starting 6 h post-challenge. Ac2-26 abolished the leukocyte infiltration, collagen deposition, granuloma formation and generation of pro-inflammatory cytokines evoked by silica; these variables were only partially inhibited by dexamethasone. KEY RESULTSA clear exacerbation of the silica-induced pathological changes was observed in ANXA1 knockout mice as compared with their wild-type (WT) littermate controls. Incubation of lung fibroblasts from WT mice with Ac2-26 in vitro reduced IL-13 or TGF-β-induced production of CCL2 (MCP-1) and collagen, but this peptide did not affect the production of CCL2 (MCP-1) by stimulated fibroblasts from formyl peptide receptor type 1 (FPR1) knockout mice. Ac2-26 also inhibited the production of CCL2 (MCP-1) from fibroblasts of FPR2 knockout mice. CONCLUSIONS AND IMPLICATIONSCollectively, our findings reveal novel protective properties of the ANXA1 derived peptide Ac2-26 on the inflammatory and fibrotic responses induced by silica, and suggest that ANXA1 mimetic agents might be a promising strategy as innovative anti-fibrotic approaches for the treatment of silicosis. IntroductionSilicosis is a lung occupational disease caused by inhalation of free crystalline silica particles over a prolonged period of time. This disease mainly affects workers in the ceramic industry, glass manufacturing, sandblasting, mining, quarrying and civil construction (Leung et al., 2012;Singer et al., 2012). Silicosis is a problem worldwide, but it is prevalent in countries of low and middle income. China had more than 500 000 cases recorded between 1991 and 1995, and 6000 new cases and more than 24 000 deaths are reported annually (Leung et al., 2012). In Brazil more than 4500 workers were reported to have silicosis between 1978 and 1998, especially in the gold-mining area in Minas Gerais (Carneiro et al., 2006). The irritative action of silica in the lungs results in the formation of nodular lesions, which may coalesce resulting in massive areas of fibrous tissue and reduction of lung elasticity (Davis, 1986). Because of its surface properties, crystalline silica leads to activation of alveolar macrophages [acting on 'scavenger' receptors such as the MARCO (macrophage receptor with collagenous structure)], epithelial cells and fibroblasts (Mossman and Churg, 1998;Fubini and Hubbard, 2003;Huaux, 2007). The granulomatous inflammation induced by silica is characterized by the accumulati...

The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

“…As mentioned before, several studies have reported a correlation between the absence of AnxA1 and tissue damage and dysfunction in different models of disease, such as gout and lung fibrosis . In agreement with that, in the context of pneumococcal pneumonia, AnxA1 KO mice presented a reduction of lung compliance and FEV 100 , alterations that were also observed in patients affected by pneumococcal pneumonia.…”

Formyl-Peptide Receptor 2/3/Lipoxin A 4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation

“…2–4 These pro-resolving mediators act at different phases of the inflammatory response and are involved in blockade of leukocyte recruitment, inhibition of cytokine release, promotion of apoptosis, stimulation of phagocytosis, and decreasing vascular permeability. 3,4 Effectors of resolution ensure that these responses remain localized within the inflamed tissue and are extinguished within an adequate timeline. Of relevance, both AnxA1/AnxA1 Ac2–26 , and LXA 4 /ATL mediate their effects through a common G protein-coupled receptor: the formyl peptide receptor 2 (Fpr2/3), also called lipoxin A 4 receptor (ALX).…”

Coal mine dust lung disease in the modern era

“…Examples of recent work in murine models of silicosis include the demonstration that the Wnt/β‐catenin pathway is required for activation of TGFβ and fibrosis . Dasatinib, the Food and Drug Administration (FDA)‐approved kinase inhibitor, has been shown to ameliorate structural changes in the lungs as well as changing macrophage phenotype in an intervention that commenced once disease had been established, as have annexin A1 mimetic peptides . The assessment of short‐term responses of single cell populations in culture systems, known as high‐throughput screening, is a particularly useful approach to drug discovery.…”

“…62 Dasatinib, the Food and Drug Administration (FDA)-approved kinase inhibitor, has been shown to ameliorate structural changes in the lungs as well as changing macrophage phenotype in an intervention that commenced once disease had been established, 63 as have annexin A1 mimetic peptides. 64 The assessment of short-term responses of single cell populations in culture systems, known as high-throughput screening, is a particularly useful approach to drug discovery. However, silicosis and pneumoconiosis represent multicellular pathological processes that are likely to be more amenable to lower throughput of drug candidates using organoid-on-achip type technologies.…”