Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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We previously identified a truncated human glucocorticoid receptor (hGR) isoform of 118 amino acids, hGR-S1(-349A), that despite lacking the major functional domains, was more hyperactive after glucocorticoid treatment than the full-length receptor. Furthermore, its 3' untranslated region (UTR) was required. To dissect the underlying mechanisms for hyperactivity, a series of hGR isoforms with consecutive deletions in the 3' UTR were created to test their transactivation potential using reporter assays. ⋯ Analysis of the 20 bp region neighboring the 1293 bp site showed a pattern: 3'UTR termination at every third base pair in this region resulted in a loss of transactivation potential while the other sites retained hyperactivity with or without glucocorticoid stimulation. Variations in the activity of an hGR isoform, due to changes in the 3' UTR sequence configuration, may provide an important link in explaining inconsistent responses to glucocorticoid treatment in individuals and ultimately enable tailored, patient-specific care. Furthermore, understanding the mechanisms underlying the cyclic hyperactivity/loss of activity phenomenon may be a step toward identifying a novel mechanism of gene regulation.
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Both acute and chronic lung injury are associated with up-regulation of the pulmonary expression of the purinergic receptors P2XR4 and P2XR7. Genetic deletion or blockade of P2XR7 attenuated pulmonary hyperinflammation, but simultaneous P2XR4 up-regulation compensated for P2XR7 deletion. Therefore, we tested the hypothesis whether genetic P2XR4 deletion would attenuate the pulmonary inflammatory response and thereby improve organ function after blunt chest trauma in mice with and without pretraumatic cigarette smoke (CS) exposure. ⋯ However, P2XR4 deletion was associated with attenuated impairment of glucose homeostasis and acid-base-status after CS exposure and chest trauma. In conclusion, genetic P2XR4 deletion failed to attenuate the acute post-traumatic pulmonary inflammatory response. The improved glucose homeostasis and acid-base-status after CS exposure in the P2XR4 group was possibly due to less alveolar hypoxia-induced right ventricular remodeling resulting in preserved liver metabolic capacity.
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Patients with inflammatory bowel disease have a unique inflammatory response to infection given the pathogenesis of these diseases and the common use of immunosuppressive therapy. ⋯ Sepsis visits with Crohn disease had improved outcomes compared with the control group. Conversely, visits with ulcerative colitis had markedly worsened sepsis-related outcomes. Further investigation is needed to determine the mechanisms underlying these clinical differences.
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Preterm sepsis is characterized by systemic bacterial invasion and inflammatory response. Its pathogenesis is unclear due to lack of proper animal models. Heme oxygenase-1 (HO-1) can affect physiologic and pathologic conditions through its anti-inflammatory, antioxidative, and anti-apoptotic properties. ⋯ Importantly, heme significantly reduced mortality from 40.9% to 6.3% (P <0.005) and gene expression of pro-inflammatory cytokines (Ccl5, Cxcl10, IL-1b, and Ifng). We conclude that the CS model can be used as a model to study preterm sepsis. Because induction of HO-1 significantly reduced mortality, we speculate that HO-1 may confer protection against sepsis in preterm infants.
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Renal ischemia-reperfusion (I/R) injury ranks as the primary cause of acute renal injury with severe morbidity and mortality. Side population (SP) cells have recently drawn increasing attention due to their critical role in injury repair and regeneration. Unfortunately, the underlying mechanism involved in renal I/R remains poorly elucidated. ⋯ Additionally, sonic hedgehog (SHH)-Gli 1 signaling was involved in SDF-1/CXCR4-mediated ABCG2 expression. When SP cells pretreated with AMD3100 were intravenously injected into I/R mice, SP cell-mediated decreases in blood urea nitrogen, serum creatinine, and histological score of kidney were noticeably attenuated, indicating that blocking CXCR4 pathway mitigated the therapeutic function of SP cells in renal I/R injury. Together, this research suggests that SDF-1/CXCR4 axis might act, via Shh-Gli1-ABCG2 signaling, as a positive regulator of SP cell-based therapies for renal I/R by Shh-Gli 1-ABCG2 signaling.