Some antioxidants including N acetylcysteine and SOD
Some antioxidants, including N-acetylcysteine and SOD, have been shown to decrease collagen deposition and protect the lungs in various animal models and even in clinical trials (Chan et al., 2013, Loomis-King et al., 2013, Rafii et al., 2013, Teixeira et al., 2008, Wang et al., 2013). Bleomycin-induced lung injury in mice leads to a significant loss of interstitial eSOD and accumulation of eSOD in BALF (Fattman et al., 2001). The finding that mice lacking eSOD have increased fibrosis in response to bleomycin suggests that depletion of interstitial eSOD after bleomycin insult may contribute to further oxidative stress in the ECM that further promotes the fibrotic response (Gao et al., 2008). Our results showed decreased activity of SOD, catalase and GSH-Px after 21 days that was probably because of inactivation of antioxidant NVP DPP 728 dihydrochloride by oxidants. We suggest that in PF, these enzymes are deregulated from 7 days after bleomycin insult because of inflammation that causes an increase in oxidant levels (Mastruzzo et al., 2002). In the elastase+bleomycin group, catalase levels were reduced after 7 days and SOD levels were reduced after 14 days. Other authors have shown that bleomycin instillation reduces catalase activity from 7 days and reduces SOD activity at 7 days and 14 days after instillation (Bannister and Bannister, 1987, Deger et al., 2007, Teixeira et al., 2008). We observed not only decreased levels of antioxidant enzymes 21 days after instillation but also decreased levels of GST. Levels of phase-II antioxidant enzymes have been shown to be described to in rats during bleomycin-induced PF (Sriram et al., 2009). GST integrates a group of phase-II antioxidant enzymes transcribed by nuclear factor erythroid 2-related factor 2 that acts as an indirect antioxidant enzyme which, among other functions, has an important role in redox balance, including in inflammatory diseases of the lung (Mazur et al., 2010, Walters et al., 2008). In the end phase of our study, GST had a protective function against PF when levels of antioxidant enzymes were reduced (particularly in the elastase+bleomycin group).
NO is the main reactive nitrogen species found in vivo. At high concentrations, NO is toxic if combined with superoxide anions because peroxynitrite is formed (Naura et al., 2010). Nitrite is an indirect marker of NO and its levels are increased in PF patients (Rihak et al., 2010). Our results corroborate those studies because the bleomycin group and elastase+bleomycin group showed progressive increased in levels of nitrite. Nitrite levels were increased on days 14 and 21, so these progressive increased may be negatively related to SOD activity. In this situation, SOD might have first been converted into peroxonitrite because the rate constant was >3.5-times faster than the dismutation of superoxide by SOD.
The present study had several limitations. First, it was generated from an in vivo model realized by combination of elastase/bleomycin treatment that mimics acute lung injury and not a chronic disease such as emphysema (elastase) and non-specific interstitial pneumonia instead of interstitial pulmonary fibrosis (bleomycin). Second, this “new model” does not engender mechanistic conclusions on the pathogenesis of the lung condition characterized by simultaneous presentation of emphysema and PF. Third, there was a lack of detailed information on MMPs and tissue inhibitor of MMPs at each time-point in all groups. Finally, the combination of PF and emphysema is a clinical syndrome associated with more severe impairment in gas exchange than either disease alone. Often, this syndrome is associated with pulmonary hypertension (WHO class III). We failed to test this condition here.
Introduction Histones are small alkaline proteins existing in eukaryotic cell nuclei. They are primarily involved in DNA packaging and regulation of DNA replication and transcription . Histones are divided into five families, i.e., H1/H5, H2A, H2B, H3, and H4, of which, H2A, H2B, H3 and H4 are the core histones, and H1/H5 are the linker histones , . Each core histone contains a C-terminal tail, a central “histone-fold” domain, and a flexible N-terminal tail . Many reports have shown that histone proteins or histone-derived peptides from various vertebrates possess antimicrobial activities , , , , , . In late 1950s, James G. Hirsch first reported that histones killed bacterial pathogens, which was later confirmed by other groups , , , . Histones kill a wide range of bacteria including Escherichia coli, Shigella, Salmonella, Staphylococci, as well as parasites , , , but the mode of killing remains unknown.