Bleomycin induces pleural and subpleural fibrosis in the presence of carbon particles

Abstract

The pathological changes in idiopathic pulmonary fibrosis (IPF) typically start in subpleural lung regions, a feature that is currently not explained. IPF, as well as bleomycininduced lung fibrosis, are more common in smokers. We hypothesised that carbon particles, which are major components of cigarette smoke that are transported to alveoli and pleural surface, might be involved in the development of subpleural fibrosis through interaction with pleural mesothelial cells.Carbon particles were administered to mice in combination with bleomycin through intratracheal and/or intrapleural injection and fibrosis was assessed using histomorphometry.Carbon administered to the chest cavity caused severe pleural fibrosis in the presence of bleomycin, whereas bleomycin alone had no fibrogenic effect. The pleural response was associated with progressive fibrosis in subpleural regions, similar to IPF in humans. Matrix accumulation within this area evolved through mesothelial-fibroblastoid transformation, where mesothelial cells acquire myofibroblast characteristics. In contrast, carbon did not exaggerate bleomycin-induced pulmonary fibrosis after combined intratracheal administration.This represents a novel approach to induce a robust experimental model of pleural fibrosis. It also suggests that carbon particles might be involved as a cofactor in the initiation and/or progression of (subpleural) pulmonary and pleural fibrosis. Mesothelial cells appear to be critical contributors to this fibrotic process.

Plasminogen Activator Inhibitor-1 Deficiency Augments Visceral Mesothelial Organization, Intrapleural Coagulation, and Lung Restriction in Mice with Carbon Black/Bleomycin–Induced Pleural Injury

“…Wildtype (WT) C57Bl/6j mice and PAI-1 2/2 mice and PAI-1 transgenic (PAI-1 Tg ) mice on a C57Bl/6j background were purchased from Jackson Laboratory (Bar Harbor, Maine). The CBB mouse model of pleural fibrosis was established as previously described in CD1 mice (10), with some modifications. Isofluorane-anesthetized C57BL/6j mice were intrapleurally injected with 100 ml of a CBB mixture (0.1 mg carbon black [Degussa AG, Frankfurt, Germany]/0.07 U bleomycin [Teva Parenteral Medicines, Irvine, CA]) prepared in 0.9% saline.…”

“…Pleural injury is characterized by the proliferation of a-smooth muscle actin (a-SMA)-expressing myofibroblasts (10,11). These cells promote the accumulation of extracellular matrix (ECM) proteins, including collagen (Col)-1 (12).…”

Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent

“…Mesothelial MT (MesoMT) is characterized by mesenchymal changes in cell morphology. Furthermore, increased expression of ␣-SMA and collagen 1 (Col-1) are hallmarks of myofibroblasts (1,2,14,19). Both ␣-SMA and Col-1 were upregulated in mesothelial cells undergoing MesoMT in vivo in a CBB-mediated model of pleural injury in which thrombin and plasmin were upregulated within the injured pleural compartment (19).…”

“…Our work and that of others has shown that pleural mesothelial cells (PMCs) contribute to the progression of PF by undergoing a process called mesothelial (Meso) mesenchymal transition (MT) (1,2,13,14,19), through which PMCs assume characteristics of myofibroblasts. Mesothelial MT (MesoMT) is characterized by mesenchymal changes in cell morphology.…”

Pleuroparenchymal fibroelastosis: one more walk on the wild side of drugs?

“…The case against causal association, includes the possibility that PPFE can develop idiopathically or, as some reports suggest, as an abreaction to infectious agents [2], as well as: due to the lack of a clear dose-response curve; development and progression of fibrosis after a free interval of several years after termination of treatment; lack of reversal with drug withdrawal; and absence of robust epidemiological support or absence of a suitable animal model [55]. Current models of pleural fibrosis use transforming growth factor-b1, bleomycin and carbon black instilled in the pleural space as the inciting agents [56,57]. Conversely, in favour of an association between alkylating agents and PPFE are: the normalcy of pre-therapy chest imaging in the study by BEYNAT-MOUTERDE et al [1]; the homogenous and consistent reports of the same distinctive drug-associated disease from different countries over the past 35 years [2]; the notion that two separate alkylating agents can produce an association with PPFE; and the occurrence of PPFE in young individuals [20,25] in whom fibrotic conditions are relatively rare.…”