Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3

Half of trauma deaths are attributable to hypovolemic circulatory collapse (HCC). We established a model of HCC in rats involving minor trauma plus severe hemorrhagic shock (HS). HCC in this model was accompanied by a 50% reduction in peak acceleration of aortic blood flow and cardiomyocyte apoptosis. HCC and apoptosis increased with increasing duration of hypotension. Apoptosis required resuscitation, which provided an opportunity to intervene therapeutically. Administration of IL-6 completely reversed HCC, prevented cardiac dysfunction and cardiomyocyte apoptosis, reduced mortality 5-fold and activated intracardiac signal transducer and activator of transcription (STAT) 3. Pre-treatment of rats with a selective inhibitor of Stat3, T40214, reduced the IL-6-mediated increase in cardiac Stat3 activity, blocked successful resuscitation by IL-6 and reversed IL-6-mediated protection from cardiac apoptosis. The hearts of mice deficient in the naturally occurring dominant negative isoform of Stat3, Stat3β, were completely resistant to HS-induced apoptosis. Microarray analysis of hearts focusing on apoptosis related genes revealed that expression of 29% of apoptosis related genes was altered in HS vs. sham rats. IL-6 treatment normalized the expression of these genes, while T40214 pretreatment prevented IL-6-mediated normalization. Thus, cardiac dysfunction, cardiomyocyte apoptosis and induction of apoptosis pathway genes are important components of HCC; IL-6 administration prevented HCC by blocking cardiomyocyte apoptosis and induction of apoptosis pathway genes via Stat3 and warrants further study as a resuscitation adjuvant for prevention of HCC and death in trauma patients

Role of vasa recta and chemical diversity in Randall’s plaque pathogenesis

International audienceBackgroundAlexander Randall identified calcium phosphate plaques in renal papillae as the origin of kidney stones. However, little is known about the early steps of Randall’s plaque formation, preceding the onset of urolithiasis. Our objectives were to characterize the composition and the initial formation site of incipient Randall’s plaque.Material and MethodsFifty-four healthy papillae from kidneys removed for cancer have been analyzed by immunohistochemistry and Von Kossa staining, Field Emission-Scanning Electron Microscopy with Energy Dispersive X-ray analysis, µ-Fourier Transform Infrared Spectroscopy, Cryo-Transmission Electron Microscopy coupled to Selected-Area Electron Diffraction and Electron Energy Loss Spectroscopy. ResultsIncipient Randall’s plaque has been observed in 72.7% of kidneys. Carbonated apatite was the main component of microcalcifications altogether with amorphous calcium phosphate and whitlockite. Incipient plaques stood in the deepest part of the papillae, around the loop of Henle tip but also vasa recta (respectively 62.4 % and 37.2 % of microcalcifications). Microcalcifications were often made of several nanocrystals inside organic material looking like microvesicles. ConclusionIncipient Randall’s plaque is frequent and appears at the tip of renal papillae, around the hairpin structure of the loop of Henle and vasa recta as well. Nanoscale analyses suggest a local nucleation process promoting nanocrystal growth in a supersaturated milieu