Intranasal Flunisolide Suppresses Pathological Alterations Caused by Silica Particles in the Lungs of Mice

Abstract

Silicosis is an occupational disease triggered by the inhalation of fine particles of crystalline silica and characterized by inflammation and scarring in the form of nodular lesions in the lungs. In spite of the therapeutic arsenal currently available, there is no specific treatment for the disease. Flunisolide is a potent corticosteroid shown to be effective for controlling chronic lung inflammatory diseases. In this study, the effect of flunisolide on silica-induced lung pathological changes in mice was investigated. Swiss-Webster mice were injected intranasally with silica particles and further treated with flunisolide from day 21 to 27 post-silica challenge. Lung function was assessed by whole body invasive plethysmography. Granuloma formation was evaluated morphometrically, collagen deposition by Picrus sirius staining and quantitated by Sircol. Chemokines and cytokines were evaluated using enzyme-linked immunosorbent assay. The sensitivity of lung fibroblasts was also examined in in vitro assays. Silica challenge led to increased leukocyte numbers (mononuclear cells and neutrophils) as well as production of the chemokine KC/CXCL-1 and the cytokines TNF-α and TGF-β in the bronchoalveolar lavage. These alterations paralleled to progressive granuloma formation, collagen deposition and impairment of lung function. Therapeutic administration of intranasal flunisolide inhibited granuloma and fibrotic responses, noted 28 days after silica challenge. The upregulation of MIP-1α/CCL-3 and MIP-2/CXCL-2 and the cytokines TNF-α and TGF-β, as well as deposition of collagen and airway hyper-reactivity to methacholine were shown to be clearly sensitive to flunisolide, as compared to silica-challenge untreated mice. Additionally, flunisolide effectively suppressed the responses of proliferation and MCP-1/CCL-2 production from IL-13 stimulated lung fibroblasts from silica-or saline-challenged mice. In conclusion, we report that intranasal treatment with the corticosteroid flunisolide showed protective properties on pathological features triggered by silica particles in mice, suggesting that the compound may constitute a promising strategy for the treatment of silicosis.

Effects of Green Tea Polyphenol Epigallocatechin-3-Gallate on Markers of Inflammation and Fibrosis in a Rat Model of Pulmonary Silicosis

“…Higher migration of immune cells into the lung in our study can partially result from elevated concentrations of chemokine CXCL1, which acts as a chemokine for neutrophils and other cells at the site of injury, and contributes to the regulation of the inflammatory response. Comparable findings were also demonstrated in in vitro exposure of bronchial cells to silica [55], as well as in silica-instilled mice [23]. Although the numbers of circulating monocytes in our study were elevated, and an intensive migration from circulation into the injured lung was expected, the percentage and absolute count of macrophages in the BALF decreased compared to the controls.…”

“…Nevertheless, considering the role of silica-induced inflammation in the pathophysiology of silicosis, the testing of novel approaches targeting inflammation and fibrosis, especially in the early stages of the disease, is particularly important. As reviewed in our article [5], promising results have been published for treatment with, for example, antifibrotic agents approved for idiopathic pulmonary fibrosis pirfenidone [15] and nintedanib [16], antioxidant N-acetylcysteine [17,18], agents blocking pro-inflammatory cytokines [19,20], inhibitors of phosphodiesterases increasing cyclic adenosine monophosphate (cAMP) or guanosine monophosphate (cGMP) [21,22], or corticosteroids [21,23].…”

In Silico Drug Repurposing in Multiple Sclerosis Using scRNA-Seq Data

“…Interestingly, for monocytes in PBMC, we found the anti-asthma drug Flunisolide, which is a corticosteroid effective for controlling chronic lung inflammatory diseases [ 52 , 53 ]. We did not find any experimental evidence of Flunisolide effects in the MS state.…”

New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

“…Flunisolide suppressed the silica-induced upregulation of macrophage inflammatory proteins (MIP)-1α/CCL-3 and MIP-2/CXCL-2, decreased TNFα and TGFβ, and reduced deposition of collagen and airway hyperreactivity to methacholine. In addition, flunisolide effectively repressed the responses of proliferation and MCP-1/CCL-2 production in IL-13-stimulated lung fibroblasts from silica-or saline-challenged mice [116].…”

“…Anakinra, given to the 37-year-old man in a dose of 100 mg/day subcutaneously for 6 months, improved his respiratory functions, oxygen saturation, and inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) [95]. Anti CD-11 antibodies [103] Agents influencing autophagy-lysosomal system Imipramine [104] Dioscin [105] Rapamycin/cAMP [106] Atractylenolide III [107] Trehalose [108] Antioxidants N-acetylcysteine [109][110][111] Corticosteroids Dexamethasone [112][113][114][115] Flunisolide [116] Endogenous glucocorticoids Annexin A1 [117] Agents increasing cAMP Roflumilast [118] Tadalafil [119] Sildenafil [115] Agents influencing TGFβ Emodin [120,121] Ponatinib [122] Table 1. Cont.…”