Effect of Platelet-Derived Growth Factor on the Development and Persistence of Asbestos-Induced Fibroproliferative Lung Disease

Abstract

Platelet-derived growth factor (PDGF) isoforms and PDGF receptor-alpha are upregulated in fibroproliferative lesions in response to asbestos exposure. To examine the functional role of PDGF in asbestos-induced lung disease, we have evaluated the impact of PDGF-B overexpression in the lung on the development of pulmonary fibrosis induced by asbestos inhalation. Transgenic mice expressing PDGF-B from the surfactant protein C promoter and wild-type C57BL/6 mice were exposed to aerosolized chrysotile asbestos fibers via three different exposure regimens: 3 consecutive days to 9 mg/m(3), once a week for 5 weeks to 12 mg/m(3), or once a week for 8 weeks to 11 mg/m(3). The 3-day exposure did not produce fibroproliferative lesions in SPC-PDGFB or wild-type mice, indicating that PDGF expression did not increase susceptibility to a subthreshold dose of asbestos. Transgenic and wild-type mice subjected to the 5-week exposure protocol exhibited similar fibrogenic lesions histologically 48 hours and 8 weeks postexposure, but lungs from transgenic mice had elevated lung hydroxyproline content 8 weeks postexposure relative to wild-type mice. In addition, SPC-PDGFB transgenic mice developed pronounced thickening of arterioles following the 5-week exposure regimen. Mice exposed to asbestos for 8 weeks and examined 10 months later showed pronounced, diffuse fibrotic lesions of terminal bronchioles and alveolar ducts, but no histological differences between transgenic and nontransgenic mice were observed. These results indicated that PDGF-B overexpression can stimulate increased collagen deposition and vascular smooth muscle hyperplasia following asbestos inhalation and that a limited exposure (8 times) to chrysotile aerosol can produce long-lasting fibrotic lesions. The 8-week exposure regimen provides an animal model that encompasses an important aspect of human asbestosis-i.e., persistence of fibrosis for long periods after cessation of asbestos exposure.

Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant,N-acetyl-l-cysteine, and novel thiol antioxidant,N,N′-bis-2-mercaptoethyl isophthalamide

“…Then, unregulated repair and remodeling process result in excessive deposition of collagen and fibronectin (Moore and Hogaboam, 2008; Rojas et al 2005). The overproliferation of the fibroblasts is signaled by an increase in the secretion of cytokines such as the tumor necrosis factor-alpha and platelet-derived growth factor (Li et al 2004; Oikonomou et al 2006). Pro-inflammatory cytokines are produced largely by the leukocytes that infiltrate the lung interstitium during the endothelial barrier dysfunction in the first stage of bleomycin-induced lung damage (Vaillant et al 1996; Warshamana et al 2002; Petri and Bixel, 2006).…”

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

“…To estimate the changes of total amount of collagen in the lungs after chlorine exposure, hydroxyproline content in mouse left lungs was measured based on published methods (22,45). Tissues were hydrolyzed in 1 ml of 6 N HCl at 100°C overnight.…”

Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

“…In some cases, the pattern of UIP can be also present ( 55 , 56 ). Some of these features are recapitulated in inhalation models in animals and have helped us understand the pathogenesis of both asbestosis and IPF ( 57 – 61 ). A single intratracheal administration of asbestos fibers mediates development of fibrosis; however, the model presents with several caveats since fibrosis that tends to be central rather than subpleural and is quite often unevenly distributed between lungs.…”