Study On The Mechanism Of Cytokine Storm In Acute Lung Injury Induced By Influenza Virus

In April 2009, a novel swine-origin influenza A (H1N1) virus (S-OIV) causing human infections broke out in Mexico and then spread globally[1]. Most patients infected with S-OIV suffered respiratory illness and some severe cases developed to acute lung injury (ALI) and even acute respiratory distress syndrome (ARDS)[2]. However, its pathogenesis remains poorly understood. Here, we report that the level of IP-10, a cytokine belonging to the CXC chemokine family, both in the serum of critical and fatal patients and the bronchoalveolar lavage fluid (BALF) of mice infected with S-OIV is significantly elevated[3]. We find that the ALI induced by S-OIV infection in Ip-10 knockout mice is significantly alleviated. We further identify that PI3K-Akt-p38 and JNK/MAPK signaling pathways are involved in the ALI mediated by IP-10 in S-OIV infected mice. Moreover, treatment with monoclonal antibodies against IP-10 ameliorates the ALI induced by S-OIV infection in mice. Taken together, our current study provides insight into the molecular mechanism of IP-10 in mediating the ALI induced by S-OIV infection and indicates that monoclonal antibodies against IP-10 could be potentially used as a therapeutic remedy for the future H1N1 swine flu pandemics.In March 2013, human infections with a novel avian origin influenza A (H7N9) virus were reported in eastern China [36]. Fever, cough and short of breath were the most common presenting symptoms. Fatal outcomes of H7N9 infections are often attributed to the severe pneumonia and acute respiratory distress syndrome (ARDS) [37,38]. Up to April 22th,2014,414 cases were reported and 81 of them died. Although cytokine storm/hypercytokinemia was reported in the 1918 pandamic influenza virus, avian influenza A (H5N1) virus and 2009 influenza A (H1N1) virus infection[3,10,11], none of them linked the cytokine storm to the disease progression and fatal outcome. There is urgent need to discover biomarkers predicting the prognosis of patients with potentially lethal flu infections, based on sound statistical analysis.We recruited 47 laboratary confirmed patients infected with avian influenza A (H7N9) virus at the First Affiliated Hospital, College of Medicine, Zhejiang University (n=40), Jiangsu province (n=6) and Shanghai city (n=1). We performed multiplex analyses of 48 cytokine and chemokine mediators in the plasmas samples from H7N9-infected patients and found that 34 of them were significantly elevated. We report for the first time that the levels of MIF, SCF, MCP-1, HGF, and SCGF-β are highly positively linked to disease severity and the profile of mediators MIF, SCF, MCP-1, HGF, SCGF-P, IP-10, IL-18, and IFN-y is an independent outcome predictor. Our results may be of great help for the treatment of influenza virus infection during the future flu pandamics.