title: Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis.
abstract: BACKGROUND
  Pulmonary 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  BLM-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.
  
  
  CONCLUSIONS
  Rac2 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.
authors: Narcy
authors: N
authors: Arizmendi
authors: Lakshmi
authors: L
authors: Puttagunta
authors: Kerri L
authors: KL
authors: Chung
authors: Courtney
authors: C
authors: Davidson
authors: Juliana
authors: J
authors: Rey-Parra
authors: Danny V
authors: DV
authors: Chao
authors: Bernard
authors: B
authors: Thebaud
authors: Pulmonary Research Group and Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. paige.lacy@ualberta.ca.
authors: Paige
authors: P
authors: Lacy
authors: Harissios
authors: H
authors: Vliagoftis
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism* / Q000401:mortality; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism* / Q000401:mortality; D020744:rac GTP-Binding Proteins / Q000172:deficiency*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D001761:Bleomycin; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein