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Cassidy Abrams posted an update 6 months, 3 weeks ago
The current study provides a brief review of sepsis and its pathophysiology, and then highlights recent findings in the therapeutic effects of MSCs and MSC-derived secretome in improving sepsis-induced organ dysfunction. Besides, eligible sepsis candidates for MSC-therapy and the latest clinical findings in these areas have been reviewed.
Endothelial cells play a major role in inflammatory responses to infection and sterile injury. Endothelial cells express Toll-like receptor 4 (TLR4) and are activated by LPS to express inflammatory cytokines/chemokines, and to undergo functional changes, including increased permeability. The extracellular signal-regulated kinase 1/2 (ERK1/2) mediates pro-inflammatory signaling in monocytes and macrophages, but the role of ERK1/2 in LPS-induced activation of microvascular endothelial cells has not been defined. We therefore studied the role of ERK1/2 in LPS-induced inflammatory activation and permeability of primary human lung microvascular endothelial cells (HMVEC). Inhibition of ERK1/2 augmented LPS-induced IL-6 and vascular cell adhesion protein (VCAM-1) production by HMVEC. ERK1/2 siRNA knockdown also augmented IL-6 production by LPS-treated HMVEC. Conversely, ERK1/2 inhibition abrogated permeability and restored cell-cell junctions of LPS-treated HMVEC. Consistent with the previously described pro-inflaining adaptor inducing IFN-β (TRIF) signaling pathways. The activation of ERK1/2 limits LPS-induced IL-6 production by HMVEC, while at the same time promoting HMVEC permeability. Conversely, ERK1/2 activation promotes IL-6 production by human monocytes. Our results suggest that ERK1/2 may play an important role in the nuanced regulation of endothelial cell inflammation and vascular permeability in sepsis and injury.
Deregulation of the immune system in sepsis plays the central role in the pathogenesis of multiple organ failure including septic lung injury. Group 2 innate lymphoid cells (ILC2s) have emerged as a new player in regulating immune homeostasis in the lung; however, the role of ILC2s in lung injury in sepsis remains poorly understood. Here, we investigated temporal changes in stimulatory and inhibitory receptor expression and intracellular type 2 cytokine expression of ILC2s in the lung using a cecal ligation and puncture mouse sepsis model. We found that IL-13 production by ILC2s, which were predominately composed of the resident natural ILC2 subset rather than the migratory inflammatory ILC2 subset, was reduced in the lungs of sepsis mice on day 1 and gradually restored through day 7. Although the expression levels of ST2 and inducible T-cell costimulator (stimulatory receptors) were high, IL-13 production by ILC2s was reduced while showing high programmed cell death 1 (PD-1) (inhibitory receptor) expressiot report showing differential costimulatory/inhibitory receptor expression on ILC2s in a septic lung in the context of an IL-33/IL-13 pathway-mediated type 2 immune response in the progression and resolution of inflammation. Our present findings contribute to a better understanding of the underlying immunological mechanism of ILC2s and may fill the critical knowledge gap regarding immune homeostasis in the lung that hampers the development of new therapeutic strategies for sepsis-induced acute lung injury.
Extracorporeal membrane oxygenation assisted cardiopulmonary resuscitation (ECPR) is proposed for cardiac resuscitation in selected cases. End-tidal carbon dioxide (ETCO2) is easily obtained during conventional cardiopulmonary resuscitation (CPR). We hypothesized that the level of ETCO2 during CPR would reflect the degree of brain and kidney damage following ECPR in experimental refractory cardiac arrest.
Ventricular fibrillation was induced in 10 pigs, followed by mechanical CPR for 45 minutes and thereafter ECPR for 180 minutes. Blood- and urine-samples, physiologic parameters, and histopathology of brain and kidney were analysed. Animals were divided into Group High (GHigh) and Group Low (GLow) according to value of ETCO2 (10mmHg) at end of CPR.
Carotid blood pressure and blood flow declined over time in both groups during CPR but was higher in GHigh. Coefficient of determination for ETCO2 and carotid blood flow was substantial (r = 0.62). The oxygen delivery index (DO2I) was higher for GHigh 444 (396-485) l/min/m as compared to GLow at 343 (327-384) l/min/m (p = 0.02) at the end of ECPR. Also, P-S100B were lower in GHigh, (p < 0.05) and GLow demonstrated worse histopathological injury in central parts of the brain (p < 0.01). During ECPR, urinary output was higher in GHigh (p < 0.05). Kidney injury marker P-nGAL increased in both groups during ECPR but was more pronounced in GLow (p = 0.03). Apabetalone concentration Renal histopathology revealed no difference between groups.
ETCO2 at the end of mechanical CPR is inversely associated with extent of brainstem and renal injury following ECPR.
ETCO2 at the end of mechanical CPR is inversely associated with extent of brainstem and renal injury following ECPR.
We hypothesize that a patient (pt) with accelerated thrombin generation, time to peak height (ttPeak), will have a greater odds of meeting critical administration threshold (CAT) criteria (> 3 packed red blood cell transfusions per 60 min interval), within the first 24 h after injury, independent of international normalized ratio (INR).
In a prospective cohort study, trauma patients were enrolled over a 4.5-year period and serial blood samples collected at various time points. We retrospectively stratified pts into three categories CAT+, CAT- but receiving some pRBC Tx, receiving no Tx within the first 24 h. Blood collected prior to Tx was analyzed for thrombin generation parameters and prothrombin time (PT)/INR.
A total of 484 trauma pts were analyzed injury severity score = 13 , age = 48 years, and 73% male. Fifty pts met criteria for CAT+, 64 pts CAT-, and 370 received no Tx. Risk factors for meeting CAT+ decreased arrival systolic blood pressure (OR 2.82 ), increased INR (OR 2.09, ) and decreased time to peak OR 2.27 ). These variables remained independently associated with increased risk of requiring Tx in a multivariable logistic model, after adjusting for sex and trauma type.
Pts in hemorrhagic shock, who meet CAT+ criteria, are characterized by accelerated thrombin generation. In our multivariable analysis, both ttPeak and PT/INR have a complementary role in predicting those injured patients who will require a high rate of Tx.
Pts in hemorrhagic shock, who meet CAT+ criteria, are characterized by accelerated thrombin generation. In our multivariable analysis, both ttPeak and PT/INR have a complementary role in predicting those injured patients who will require a high rate of Tx.