P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

• Main Authors: Patricia Teixeira Santana (Author), Tatiana Luna-Gomes (Author), Marcos Vinicius Rangel-Ferreira (Author), Augusto Shuiti Tamura (Author), Carolyne Lalucha Alves Lima Da Graça (Author), Mariana Nascimento Machado (Author), Walter Araujo Zin (Author), Christina Maeda Takiya (Author), Debora Souza Faffe (Author), Robson Coutinho-Silva (Author)
• Format: Book
• Published: Frontiers Media S.A., 2020-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2020.00301
• Keywords: silica particles; silicosis; purinergic receptors; P2Y12 receptor; ADP; clopidogrel; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 11 (2020)

Silicosis is an occupational lung disease caused by inhalation of silica particles. It is characterized by intense lung inflammation, with progressive and irreversible fibrosis, leading to impaired lung function. Purinergic signaling modulates silica-induced lung inflammation and fibrosis through P2X7 receptor. In the present study, we investigate the role of P2Y12, the G-protein-coupled subfamily prototype of P2 receptor class in silicosis. To that end, BALB/c mice received an intratracheal injection of PBS or silica particles (20 mg), without or with P2Y12 receptor blockade by clopidogrel (20 mg/kg body weight by gavage every 48 h) - groups CTRL, SIL, and SIL + Clopi, respectively. After 14 days, lung mechanics were determined by the end-inflation occlusion method. Lung histology was analyzed, and lung parenchyma production of nitric oxide and cytokines (IL-1β, IL-6, TNF-α, and TGF-β) were determined. Silica injection reduced animal survival and increased all lung mechanical parameters in relation to CTRL, followed by diffuse lung parenchyma inflammation, increased neutrophil infiltration, collagen deposition and increased pro-inflammatory and pro-fibrogenic cytokine secretion, as well as increased nitrite production. Clopidogrel treatment prevented silica-induced changes in lung function, and significantly reduced lung inflammation, fibrosis, as well as cytokine and nitrite production. These data suggest that inhibition of P2Y12 signaling improves silica-induced lung inflammation, preventing lung functional changes and mortality. Our results corroborate previous observations of silica-induced lung changes and expand the understanding of purinergic signaling in this process.