The American journal of pathology
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Although bone marrow-derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. ⋯ A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P ≤ 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial-related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response.
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Necroptosis is a recently discovered programmed necrosis. Evidence demonstrated the importance of necroptosis in neuronal cell death. Necrostatin-1 is a specific inhibitor of necroptosis. ⋯ Treatment with necrostatin-1 inhibited the induction of receptor-interacting protein kinase phosphorylation after RD (a biomarker of necroptosis). Finally, electroretinographic recording proved that necrostatin-1 contributed to objective functional improvement after RD. These findings indicate that necrostatin-1 is a promising therapeutic agent that protects photoreceptors from necroptosis and improves functional outcome.
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The Eph/ephrin receptor-ligand system plays an important role in embryogenesis and adult life, principally by influencing cell behavior through signaling pathways, resulting in modification of the cell cytoskeleton and cell adhesion. There are 10 EphA receptors, and six EphB receptors, distinguished on sequence difference and binding preferences, that interact with the six glycosylphosphatidylinositol-linked ephrin-A ligands and the three transmembrane ephrin-B ligands, respectively. The Eph/ephrin proteins, originally described as developmental regulators that are expressed at low levels postembryonically, are re-expressed after injury to the optic nerve, spinal cord, and brain in fish, amphibians, rodents, and humans. ⋯ Specifically, EphA2/ephrin-A1 signaling in the lung may be responsible for pulmonary inflammation in acute lung injury. A role in T-cell maturation and chronic inflammation (heart failure, inflammatory bowel disease, and rheumatoid arthritis) is also reported. Although there remains much to learn about Eph/ephrin signaling in human disease, and specifically in injury and inflammation, this area of research raises the exciting prospect that novel therapies will be developed that precisely target these pathways.