Abstract
Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC) apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1) induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control) nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury.
Highlights
Lung vascular injury is a critical component of many insults that cause ALI/ARDS [1]
Having confirmed that the amounts of MPs from both control and LPS samples were comparable, we subjected them to human pulmonary microvascular endothelial cell (HPMVEC) and analyzed for cell death
Despite remarkable advances in ARDS/ALI research highlighting the many facets of innate immunity, our understanding of the complexity and critical importance of innate responses in the context of infectious challenges and acute lung injury is rudimentary
Summary
Lung vascular injury is a critical component of many insults that cause ALI/ARDS [1]. Recent published investigations have shown programmed cell death or apoptosis to be important factors in endothelial damage. Some recent lines of evidence suggest the activation of Fas (CD95)/Fas ligand (FasL; CD178) system may play a pivotal role in lung vascular injury [7,8,9]. Despite increased awareness and investigation that provide insight into pathogenesis of cell injury and immune responses in ARDS, there are several gaps in our knowledge; as a result of which there is currently no effective pharmacologic therapy. The actual mechanisms leading to injury remain incomplete and are likely to involve a combination of necrosis and apoptosis
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