RESUMEN
Fibroblast to myofibroblast transdifferentiation mediates numerous fibrotic disorders, such as idiopathic pulmonary fibrosis (IPF). We have previously demonstrated that non-muscle myosin II (NMII) is activated in response to fibrotic lung extracellular matrix, thereby mediating myofibroblast transdifferentiation. NMII-A is known to interact with the calcium-binding protein S100A4, but the mechanism by which S100A4 regulates fibrotic disorders is unclear. In this study, we show that fibroblast S100A4 is a calcium-dependent, mechanoeffector protein that is uniquely sensitive to pathophysiologic-range lung stiffness (8-25 kPa) and thereby mediates myofibroblast transdifferentiation. Re-expression of endogenous fibroblast S100A4 rescues the myofibroblastic phenotype in S100A4 KO fibroblasts. Analysis of NMII-A/actin dynamics reveals that S100A4 mediates the unraveling and redistribution of peripheral actomyosin to a central location, resulting in a contractile myofibroblast. Furthermore, S100A4 loss protects against murine in vivo pulmonary fibrosis, and S100A4 expression is dysregulated in IPF. Our data reveal a novel mechanosensor/effector role for endogenous fibroblast S100A4 in inducing cytoskeletal redistribution in fibrotic disorders such as IPF.
Asunto(s)
Fibrosis Pulmonar Idiopática , Mecanotransducción Celular , Miofibroblastos , Proteína de Unión al Calcio S100A4 , Animales , Ratones , Transdiferenciación Celular , Fibrosis , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Pulmón/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patología , Proteína de Unión al Calcio S100A4/genética , Proteína de Unión al Calcio S100A4/metabolismoRESUMEN
Sepsis is a systemic inflammatory response that requires effective macrophage metabolic functions to resolve ongoing inflammation. Previous work showed that the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), mediates macrophage phagocytosis and cytokine production in response to lung infection. Here, we show that TRPV4 regulates glycolysis in a stiffness-dependent manner by augmenting macrophage glucose uptake by GLUT1. In addition, TRPV4 is required for LPS-induced phagolysosome maturation in a GLUT1-dependent manner. In a cecal slurry mouse model of sepsis, TRPV4 regulates sepsis-induced glycolysis as measured by BAL fluid (BALF) lactate and sepsis-induced lung injury as measured by BALF total protein and lung compliance. TRPV4 is necessary for bacterial clearance in the peritoneum to limit sepsis-induced lung injury. It is interesting that BALF lactate is increased in patients with sepsis compared with healthy control participants, supporting the relevance of lung cell glycolysis to human sepsis. These data show that macrophage TRPV4 is required for glucose uptake through GLUT1 for effective phagolysosome maturation to limit sepsis-induced lung injury. Our work presents TRPV4 as a potential target to protect the lung from injury in sepsis.
Asunto(s)
Transportador de Glucosa de Tipo 1 , Glucólisis , Lesión Pulmonar , Macrófagos , Sepsis , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Sepsis/metabolismo , Sepsis/complicaciones , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Ratones , Lesión Pulmonar/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Humanos , Masculino , Glucosa/metabolismo , Fagosomas/metabolismo , Líquido del Lavado Bronquioalveolar , Lipopolisacáridos/farmacología , Fagocitosis , Modelos Animales de Enfermedad , Pulmón/metabolismo , Pulmón/patología , Pulmón/inmunologíaRESUMEN
OBJECTIVE: The goal was to examine, in an all female sample, possible mechanisms for the relationship between a history of childhood sexual abuse and the likelihood of perpetrating sexual abuse as an adult. It was hypothesized that Borderline and Antisocial Personality Disorder tendencies would mediate the relationship between these two forms of abuse. METHOD: One hundred forty two female participants (61 sex-offenders and 81 non-sex offenders) were recruited from a woman's prison in the Midwest. The participants completed measures that included a childhood history of sexual abuse, socially desirable responding, primary and secondary psychopathy, and Borderline Personality Disorder tendencies. RESULTS: Participants in the sexual-offender group reported more frequent instances of childhood sexual abuse (p<.05, M=16.4, SD=7.2) than participants in the non-sex offender group (M=12.2, SD=7.7). Consistent with past research, childhood sexual abuse was related to Borderline Personality Disorder tendencies (r=.36, p<.01). However, discriminant function analyses did not reveal support for our mediational hypotheses. Finally, the results indicated that participants in the sexual-offender group experienced childhood sexual abuse for a greater duration of time (p<.05, M=27.8, SD=20.5 months) than participants in the non-sex offender group (M=16.6, SD=10.4). CONCLUSIONS: This study replicated previous research conducted on all male samples suggesting that the nature of the sexual abuse suffered in childhood is an important variable in predicting future sexual abuse perpetration.