Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis

Abstract

BackgroundPulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis.MethodsTo determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2 -/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content.ResultsBLM-treated rac2 -/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2 -/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2 -/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2 -/- and WT and mice that survived to day 21.ConclusionRac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the physiological changes seen in the airways after BLM-induced injury.

Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-κB and TGF-β1/Smad-2/-3 pathways

“…In this study, we first evaluated the effects of salidroside on BLM-induced lung injuries by examining the histological changes in rats. Our data in keeping with previous studies (Arizmendi et al 2014;Della Latta et al 2015) showed a significant structure distortion of lung tissues in rats challenged with BLM. Abnormal infiltration of inflammatory cells and overproduction of TNFα and IL-6 as well as collagens were presented in BLM-treated lungs.…”

Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro

“…Bleomycin (BLE) is a medicine applied to treat a variety of human diseases. But it has severe side effects of inducing pneumonitis and fibrosis [32]. Therefore, BLE is usually used to establish acute lung injury model in vivo [33].…”

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…The enhanced effect of α7 nAChR agonist GTS-21 on TGF-β-induced expression of Fstl1, Acta2 and Col1a1 was diminished by deletion of Chrna7 (Figures 11C-F). It takes approximately 3 wks to establish a mouse model of BLM-induced lung fibrosis (59,60). The mice challenged with high-dose bleomycin usually died after 7 d; therefore we had to euthanize mice by 7 d. The first week is the early BLM-induced lung fibrosis mouse model.…”