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Funding
Disclosure of interest
Acknowledgments
Introduction Pulmonary fibrosis (PF) is a chronic disease characterized by extensive deposits of the extracellular matrix (ECM) that can impair the architecture and function of the lungs (Cavazza et al., 2010). Imbalance between the proliferation and apoptosis of fibroblasts results in increased synthesis/deposition of the ECM against degradation, leading to accumulation of collagen fibers and reduction of the respiratory surface (Todd et al., 2012). Development of PF may be rapid and, once installed, and patient survival is ≈3 years. PF can also display alternating long periods of stability as well as short episodes of exacerbation (Rafii et al., 2013). Susceptibility to PF appears to be related to the interaction between multiple factors, such as genetic predisposition (Santangelo et al., 2013), oxidative stress (Kliment and Oury, 2010) and the inflammatory response (Homer et al., 2011). Bleomycin is a glycosylated peptide antibiotic produced by the bacterium Streptomyces verticillus and is used as an anticancer agent. However, there is a common reported side effect in that PF is induced (Moore et al., 2013) even though not all patients treated with bleomycin manifest it (Fernandez Perez, 2012). Several agents have been used to induce PF, such as irradiation (Epperly et al., 2003), silica (Shimbori et al., 2010) and bleomycin (Manoury et al., 2005). Participation of inflammation and oxidative stress in PF in animal models is well established (Moeller et al., 2008). Studies have demonstrated bleomycin-induced PF resistance in BALB/c mice that is due to the activity and expression of superoxide dismutase (SOD) (Santos-Silva et al., 2012). Pulmonary Colistin Methanesulfonate sodium salt synthesis is a chronic disease characterized by permanent destruction of the respiratory areas (e.g., bronchioles, alveolar ducts, alveoli) that impair the architecture and function of the lungs (Bezerra et al., 2011). Our research team has developed two experimental models of emphysema that elicit changes similar to those observed in human emphysema: exposure to cigarette smoke (Valenca et al., 2004) and instillation of porcine pancreatic elastase (PPE) (Lanzetti et al., 2012). Participation of inflammation and oxidative stress in emphysema in animal models has been documented, and studies have demonstrated major participation of tumor necrosis factor (TNF)-α (Churg et al., 2002), matrix metalloproteinase (MMP)-12 (Valenca and Porto, 2008), nuclear factor-kappa B (Valenca et al., 2006) and oxidative stress (Rueff-Barroso et al., 2010). Some scholars hypothesize that PF may be associated with a preexisting inflammatory disease (e.g., pulmonary emphysema), or that emphysema and fibrosis develop in mice spontaneously, after exposure to cigarette smoke, or after single treatment with bleomycin (Bartalesi et al., 2005, Cavarra et al., 2001, Gardi et al., 1992, Lucattelli et al., 2005). PF can occur also in smokers exposed to a causative agent of fibrosis (Silva et al., 2008), so some individuals may develop pulmonary emphysema and PF simultaneously. We wished to produce an animal model of middle-aged smokers (using elastase) exposed to unsanitary conditions of toxic inhalants or treated with bleomycin. We also wanted to find evidence of emphysema lesions together with fibrotic areas, and to see if previous treatment with elastase reduced bleomycin-induced PF at 21 days.
Material and methods
Results
Discussion Recently, studies have shown progression of bleomycin-induced PF in several experimental models (Lucattelli et al., 2005, Luzina et al., 2013, Manoury et al., 2005, Martins et al., 2009). However, until now, little evidence of cure for PF in humans has been discussed. In the study, we sought to combine mild elastase-induced emphysema with bleomycin-induced PF in mice. We wanted to find evidence of emphysema lesions together with fibrotic areas, and to see if previous treatment with elastase reduced bleomycin-induced PF at 21 days. Interestingly, at 21 days, we documented major bleomycin-induced lung lesions and large ECM deposits. We do not suggest that elastase is a treatment for PF, but the mechanisms of ECM remodeling could be explored further using a similar experimental design with other therapeutic drugs.