Fig. 6.

The hypothesized mechanistic model of extracellular histones in mediating cellular injury and systemic inflammation associated with ARDS. It is proposed that various insults (lung specific or extrapulmonary) cause extensive death of lung endothelial and/or epithelial cells or induce inflammatory cell infiltration, which subsequently leads to massive release of histones into extracellular spaces. The presence of high levels of extracellular histones may exert multiple biological effects including direct cytotoxicity, platelet aggregation, and activation of systemic inflammation by promoting cytokine production, which in turn attracts more inflammatory cells and enhance inflammation that eventually contribute to the pathogenesis of ARDS