Elucidation of neutrophils-mediated effect of MMP-2 on lung epithelial cells; implications for acute respiratory distress syndrome and severe dengue pathogenesis.

Dengue is a vector-borne viral fever that is spread by the bites of Aedes mosquitoes. Matrix metalloproteinases (MMPs) play a significant role in the beginning and development of dengue pathogenesis, but their precise functions with respect to neutrophil-associated lung pathology are not understood. In the present study, we, for the first time, report that in-vitro cultured neutrophils secrete MMP-2 in response to dengue virus NS1 antigens in culture medium (the secretome). We have assessed the effect of neutrophil secretome on the apoptosis of A549 lung epithelial cells and found that it causes their death. This suggested that neutrophils cause apoptosis of lung epithelial cells via MMP-2-mediated mechanisms. The exposure of purified MMP-2 protein has also caused cell death of A549 epithelial cells by increasing the mRNA expression pattern of apoptotic genes. Atorvastatin (10 µM) treatment attenuated the change in the release of MMP-2 and further decreased the apoptosis of lung epithelial cells. Interestingly, it was seen that MMP-14 alone and NS1 antigen alone do not cause the apoptosis of lung epithelial cells, ruling out their direct involvement. The interactions of CD31-positive neutrophils in lungs and MMP-2 expression were also found in NS1-injected mice, supporting their role in in-vivo situations. In conclusion, this study suggests that the interaction of NS1-activated neutrophils with the alveolar epithelial cells participates in the lung pathogenesis involved in the acute respiratory distress syndrome (ARDS) in severe dengue disease. The present results are encouraging; however, further investigations are required to clarify the findings.