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  • Initially we ascertained that if


    Initially, we ascertained that if the dose of elastase was sufficient to cause pulmonary emphysema, then pulmonary emphysema could be maintained throughout the study. We found that elastase at 3U was sufficient to cause emphysema that remained over 35 days. In this experimental design of lung disease, we observed increased numbers of vip receptor (i.e., enlarged alveolar space; a major characteristic of pulmonary emphysema) in the elastase+bleomycin group at 7 days. Subsequently, we observed marked deposition of the ECM (14 days) as quantified by the volume density of collagens. Finally, we observed a similar pattern to that of the control group, suggesting a reduction in the number of collagen deposits. One of the main factors implicated in the pathophysiology of PF is inflammation (Gasse et al., 2011, Kikuchi et al., 2011). Other theories have been developed to explain the progression of PF based on clinical and histopathologic findings in human disease, as reviewed by Gogali and Wells (2010). Correlations between biochemical markers and molecular biology with histopathologic findings may help to elucidate the pathophysiologic mechanisms of PF and contribute to future therapies. From this viewpoint, our results are in accordance with studies after instillation of bleomycin that demonstrated increases in levels of IL-1β and IL-6 from day 3, with a peak at 7 days, and then progressive decreases at 14 days and 21 days (Gasse et al., 2011, Hoshino et al., 2009, Rhee et al., 2011). Nevertheless, collagen deposition may be a result of the balance of expression of other growth factors and cytokines during this initial stage and subsequent fibroblastic stages (Kaminski et al., 2000, Zhao et al., 2009). It has been suggested that inflammatory mediators may be retained by the ECM, resulting in prolonged repair with excessive deposition or decreased remodeling of collagen. Growth factors such as IL-1β are retained by the ECM to perpetuate proliferation and differentiation of cells that may favor fibrosis by acting with other pro-inflammatory cytokines (e.g., IL-6), thereby leading to progressive and disorganized wound repair in lung tissue (Bringardner et al., 2008, Kolb et al., 2001). Bleomycin administration has been shown to result in greater expression of IL-1β in mice and to be associated to inflammation and fibrosis (Barlo et al., 2011, White et al., 2008). IL-6 participates in the inflammatory process of PF via the Erk 1/2 signaling pathway to induce fibroblast proliferation (Moodley et al., 2003). Increases in IL-6 levels have been observed in the BALF of animals in the acute phase, and have an important role in remodeling of the pulmonary architecture, especially in the first 24h (Manoury, Nenan, 2005), and IL-6 levels remain high 3 days after bleomycin instillation (O’Donoghue et al., 2012). Our results showed no participation of IL-6 in PF progression, but this result may have been associated with the origin of samples. Our samples for ELISA were from tissue, not from BALF. We evaluated cytokines that act in the acute phase upon tissue repair. However, we should not exclude the importance of the balance of expression with other inflammatory cytokines that may also contribute to PF progression. Oxidative stress is implicated as an important molecular mechanism underlying PF. However, the causal role of reactive oxygen species (ROS) released from environmental exposures and inflammatory/interstitial cells in mediating PF as well as how best to target an imbalance in ROS production during fibrosis is not established (Cheresh et al., 2013, Cui et al., 2011, Santos-Silva et al., 2012). We observed impairment of endogenous antioxidant enzymes in PF. Initially, SOD activity in lung tissue homogenates decreased 7 days after bleomycin instillation. Studies have shown that a specific type SOD is impaired in this experimental model (e.g., expression of extracellular-SOD (eSOD) in the lung) (Santos-Silva et al., 2012). This reduction of SOD activity could be due to enzyme inactivation by oxidants (De Raeve et al., 1997). Use of lecithinized SOD has been shown to suppress bleomycin-induced PF in a dose-dependent manner (Tanaka et al., 2009).