RESUMO
Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism. Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.
Assuntos
Injúria Renal Aguda/genética , Síndrome de Esmagamento/genética , Ativação Plaquetária/genética , Rabdomiólise/genética , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Citrulinação/genética , Síndrome de Esmagamento/etiologia , Síndrome de Esmagamento/patologia , DNA/genética , DNA/metabolismo , Modelos Animais de Doenças , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/metabolismo , Heme/metabolismo , Histonas/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Músculo Esquelético/lesões , Músculo Esquelético/patologia , Mioglobina/genética , Espécies Reativas de Oxigênio/metabolismo , Rabdomiólise/complicações , Rabdomiólise/patologia , Vesículas Secretórias/genéticaRESUMO
Using in situ hybridization histochemistry, we characterized the spatiotemporal gene expression patterns of leukemia inhibitory factor (LIF) and glial cell line-derived neurotrophic factor (GDNF), and their receptor components (LIFR, GFR-alpha1, RET) induced in muscle cells, intramuscular nerves, and motoneurons in the regeneration processes of both muscle cells and nerves following muscle contusion. Muscle contusion induced upregulation of GDNF and GFR-alpha1 mRNAs in Schwann cell-like cells in the intramuscular nerves and of LIFR mRNA in damaged muscle cells. LIFR, GFR-alpha1, and RET mRNA expressions in motoneurons were upregulated following muscle contusion. Muscle contusion also induced more rapid, prominent transactivations of GFR-alpha1 and RET genes in motoneurons than did sciatic nerve axotomy. These findings suggest that rapid and prominent upregulation of the receptor components for LIF and GDNF in motoneurons is important for the regeneration of intramuscular motor nerves damaged by muscle contusion.
