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    • Our data indicated that CRP may be associated

    2018-10-23

    Our data indicated that CRP may be associated with tissue lesions. In addition to hepatic synthesis (Pfafflin and Schleicher, 2009), CRP can be synthesized by lung EMD638683 cost (e.g. epithelial cells, lymphocytes) (Ramage et al., 2004; Marc et al., 2004). However, local production in extrahepatic synthesis of CRP may be a process of localized inflammation and a marker for local cellular damage (Juma et al., 2011). Tissue studies have shown that extensive diffuse alveolar damage is the most notably histological feature in severe fatal cases with avian influenza infection. The alveolar damage was accompanied by extensive diffusion, although the distribution of virus was scattered or rare in lung tissue of fatal cases (Nakajima et al., 2013). Excessive host response including virus-induced cytokine dysregulation contributed to the pathogenesis of severe influenza disease (Lee et al., 2009; Gao et al., 2013b; Narasaraju et al., 2011). In this study, CRP+ cells presented extensive distribution in lung tissues of H5N1 or H5N6 fatal cases in addition to higher CRP levels in fatal cases. In addition, CRP enhanced induction of proinflammatory factors in THP-1 cells, and increased the expression of apoptosis gene in H5N1-infected A-549 cells in the Transwell insert co-culture system. Inflammation is a time-dependent process, usually starting locally, and is recognized centrally via blood-borne mediators (Pfafflin and Schleicher, 2009). Generally, proinflammatory cytokines appear within 1h after the start of infection, and synthesis of CRP starts 6 to 8h after onset (Pfafflin and Schleicher, 2009). CRP is produced in response to stimulation by proinflammatory factor (e.g. IL-6, tumor necrosis factor alpha, interferon gamma, or IL-1) (Ramage et al., 2004; Lelubre et al., 2013). Previous reports have shown that both IL-6 and IP-10 have significantly higher levels in H5N1 or H7N9 patients compared with healthy volunteers (Zhou et al., 2013; Deng et al., 2008), and may represent a candidate molecule for immunotherapy in the setting of severe respiratory tract infection (Mok et al., 2014; Zeng et al., 2005). The levels of elevated cytokines were positively related to viral load in patients during acute duration (de Jong et al., 2006; Sirinonthanawech et al., 2011). In this study, CRP enhanced phagocytosis of THP-1 cells to infected virus in a co-culture system with H5N1 infection, and elevated the expression of the detected IL-6 and IP-10 in THP-1 cells. Hence, CRP may relate to deteriorated inflammation as well as tissue lesions in severe influenza infection when a high viral load is produced in individuals with lethal influenza infection. Additionally, we found that enhanced CRP levels were correlated with downregulated expression of LDHB in sera of infected mice. The function of LDHB, which is consistent with an increased glycolytic phenotype, is required to maintain cell growth (Drent et al., 1996; McCleland et al., 2013). In normal tissues, LDHB is expressed in the liver, red blood cells, kidney, and heart. Its inhibition may have deleterious consequences including correlating with unfavorable survival diseases (Dawson et al., 1964; Markert et al., 1975; Chen et al., 2015). In this study, high doses of compound 1,6-bis PC treatment slightly restored the levels of LDHB in sera of infected mice whereas PR8 infection decreased LDHB level in mice. In addition, down-regulated LDHB levels correlated with increased weight loss of infected mice. Therefore, CRP-mediated immune response involved multiple sites, worsening the severity of lethal influenza infection. Animal experiments showed that 1,6-bis PC can improve the severity of illness and mortality of mice infected with lethal influenza virus in this study. Compound 1,6-bis PC, a derivative of CRP-ligand phosphocholine, can prevent dissociation of pCRP, and subsequently inhibit the generation and proinflammatory activity of mCRP. A previous study has showed that 1,6-bis PC can inhibit mCRP deposition and inflammation in rat myocardial infarction (Thiele et al., 2014). In the current study, intraperitoneal 1,6-bis PC treatment lightened the inflammatory lesions in lung tissues of mice infected with lethal influenza virus while reducing the production of CRP. In contrast, 1,6-bis PC treatment alleviated the mortality of infected mice significantly, and improve weight loss and recovery in mice. Therefore, CRP may be a target for management of severe influenza diseases.