IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Abstract

Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13–PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13–PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13–PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13–PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13–PE. In addition, IL-13–PE inhibited both IL-13–induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13–PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

“…The increase in airway resistive pressure (ΔP1,L) may have been due to the greater number of cells in the bronchi associated with areas of lumen obstruction (Faffe et al, 2001; Borges et al, 2002; Maron-Gutierrez et al, 2011; Lopes-Pacheco et al, 2013; Cruz et al, 2016). Bosutinib decreased both Est,L and ΔP2,L likely due to reduction in alveolar collapse, interstitial edema, thickening of alveolar septa, cell infiltration and collagen fiber content, whereas Δ P 1,L did not change after therapy which may be attributed to the presence of the silica particle adhere to the airway and airway hyperreactivity (Ferreira et al, 2013). …”

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

“…Animals were then instilled intranasally with silica particles (10 mg 50 μL −1 ; SigmaAldrich Corp., St Louis, MO, USA; 0.5-10 μM) and the control group received a similar volume of sterile saline (NaCl 0.9%) (Ferreira et al, 2013). Analyses were performed 7 days post-silica instillation.…”

“…This ultimately leads to the development of fibrosis (Mariani et al, 1996;Mossman and Churg, 1998). The inflammatory response is followed by fibrosis with the pivotal involvement of lung fibroblasts, which proliferate and produce extracellular matrix including interstitial collagen, laminin and fibronectin (Ferreira et al, 2013). Once the fibrosis has developed, there is no cure and the only the clinical approach is to manage the symptoms.…”

Effects of bone marrow-derived mesenchymal stem cells on the autophagic activity of alveolar macrophages in a rat model of silicosis

“…AM injury is a crucial factor in the development of silicosis (10). A previous study (11) extracted AMs using a BAL in situ technique, and then performed in vitro transfection of the cells with SiO2 in order to establish a model of SiO2 damage for subsequent analysis (12). The disadvantage of this approach is that the cells have been removed from the native environment of the organism, in which coexisting cells exert a variety of effects and interactions.…”