Exposure to exertional heat stroke (EHS) has been linked to increased long-term decrements of health. Epigenetic reprogramming is involved in the response to heat acclimation; however, whether the long-term effects of EHS are mediated by epigenetic reprogramming is unknown. r In female mice, we observed DNA methylation reprogramming in bone marrow-derived (BMD) monocytes as early as 4 days of recovery from EHS and as late as 30 days compared with sham exercise controls. r Whole blood, collected after 30 days of recovery from EHS, exhibited an immunosuppressive phenotype when challenged in vitro by lipopolysaccharide. r After 30 days of recovery from EHS, BMD monocytes exhibited an altered in vitro heat shock response. r The location of differentially methylated CpGs are predictive of both the immunosuppressive phenotype and altered heat shock responses.
Exertional heat stroke (EHS) is a serious illness and a common occurrence for military personnel, athletes, and occupational workers. Innate immunity is vital for cell survival and tissue repair needed for recovery following EHS. Previously, our group revealed a unique cytokine response to EHS where circulating interleukin‐6 (IL‐6) peaked at 0.5 h post EHS; however, little is known about the acute phase response, a subsequent response to IL‐6 signaling. Therefore, we hypothesized that EHS would induce an acute phase response that would be observed in skeletal muscles, hepatocytes, and in the circulation. Purpose To determine if acute phase proteins (APPs), fibrinogen, lipocalin, and serum amyloid A1 (SAA1) are expressed in liver and skeletal muscle following EHS and whether these result in their accumulation in the circulation. Methods Mice were subject to a standardized EHS protocol using a forced running wheel. While running, the mice experienced environmental temps of 37.5 (EHS) or 22.5 (exercise control) until they experienced loss of consciousness (at a core temperature of ~42.2). The tibialis anterior, soleus, liver, and plasma were collected from the mice (n = 8/group) at 0.5, 3, 24, 96, 216, or 336 h post‐EHS. Tissue samples from exercise controls were retrieved at 3 and 96 h post exercise. Results Using protein immunoblots, a significant increase of SAA1 was observed in liver at 3 h of recovery and peaked at 24 h when compared to the exercise control (2.4 ± 1.2*, 2.5 ± 1.4* vs. 0.1 ± 0.1 AU/total protein; respectively). Moreover, circulating SAA1 was observed at the 3 h time point (5.0 ± 3.8 AU/TP). No difference for SAA1 was observed for any other time points when compared to the control. In the liver, fibrinogen, and lipocalin were undetectable for any of the recovery timepoints. No acute phase proteins were detected in skeletal muscle; although, preliminary data revealed that SAA1 expression is elevated in skeletal muscle during sepsis. Conclusion A single episode of EHS alters the expression of SAA1 in mouse liver and plasma. This observation is consistent with an acute phase response to thermal damage, in response to IL‐6 signaling, initiating cell survival and tissue repair pathways needed for recovery. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Esta tese de Doutorado em Direito sela um período inestimável da minha própria história. Foi um período de aprendizado e de sacrifícios, de êxitos e de fracassos. Acima de tudo, foi um período que demonstrou que, sem o investimento de tantas pessoas, eu jamais teria as condições necessárias para estar aqui. Agradeço em primeiro lugar a Deus, o Princípio e o Fim de todas as coisas. Se hoje eu concluo este Doutorado em Direito, foi graças à misericórdia desse Deus tremendo, do meu Senhor e Salvador Jesus Cristo, que eu o pude concluir. Sem Deus, eu nada seria e nada poderia conquistar. Agradeço também a toda a minha família pelo seu amor e carinho, em especial aos de casa: meus pais, Marcelino e Elsa, e minhas irmãs, Amanda, Jéssica e Thiliê. Entre todos eles, registro o meu agradecimento profundo e especial a meu pai, Marcelino. A educação que me deu, os valores que inspirou em mim e o amor sacrificial com que me amou e me ama são as arestas que me formaram como homem. Agradeço a amigos e amigas que, em diferentes momentos dessa minha jornada, me acompanharam e torceram pelo meu sucesso (até mesmo a distância, durante a pandemia do vírus Covid-19 em 2020).
Exertional heat stroke (EHS) is a life‐threatening medical event that requires immediate care. Current guidelines recommend return‐to‐physical activity following EHS in only a few weeks, with full return‐to‐physical activity around three months. We have previously observed that a single episode of EHS in mice leads to a long‐lasting, altered epigenetic signature in progenitor monocytes and in skeletal muscle DNA, as well as marked alterations to the heart’s metabolomic profile. These observations occur with no outward indications of underlying disorders in normal mouse behavior or appearance. Therefore, the physiologic manifestations of the epigenetic changes remain unknown. PURPOSE To establish a link between the epigenetic changes we observe and an inflammatory cell phenotype. To do this we tested whether a single EHS exposure leads to a sustained and aberrant inflammatory response in blood immune cells, one month after EHS exposure. METHODS Sixteen mice were either subjected to a standardized EHS protocol using a forced running wheel (environmental temp: 37.5°C, 40% humidity) or a matched exercise control trial (EXC) (22.5°C). The EHS mice achieved peak core temps of ~42.2°C, accompanied by transient loss of consciousness. Mice were sacrificed after 30 days of recovery. Blood was collected via cardiac stick. One aliquot of collected blood was exposed to 1 ng/mL of lipopolysaccharide (LPS) in solution of RPMI and Pen/Strep and placed in a 5% CO2 incubator at 37.0°C for 18 hours; the other aliquot served as a control (no LPS). Thereafter, blood was centrifuged, and plasma was collected and frozen in −80°C until cytokine analysis by Luminex. Cytokine concentration in both the LPS and no LPS blood conditions were normalized per 100,000 cells in each individual mouse. Reported as mean ± SD. RESULTS In EXC group, LPS increased [IL‐6] by 30.01 ± 14.5 pg whereas in the EHS group LPS increased [IL‐6] by only 7.0 ± 17.4 pg (P=0.003). In EXC group, LPS increased [TNF‐a] by 0.33 ± 0.22 pg, whereas in the EHS group LPS increased [TNF‐a] by only 0.11 ± 0.11 pg (P=0.001). Genes integral to TLR‐4‐mediated secretion of IL‐6 and TNF‐a that have differentially methylated CpG sites include: TLR4 (59 sites), Nfkb1 (38), Foxo1 (81), IL‐6 (4), Myd88 (7) and a variety of JAK/Stat and MAPK proteins; some of these CpG sites reside within the promoter region of their respective gene. CONCLUSION We have shown a blunted inflammatory response 30 days after a single episode of EHS. This abnormal inflammatory response in mature blood‐residing immune cells may be a manifestation of the unique EHS‐induced DNA methylation pattern we observed within immature progenitor monocytes. Our findings suggest that responsiveness of the immune system could be considered as a potential biomarker for both return‐to‐physical activity and long‐term care, post‐EHS. Support or Funding Information DOD Grant BA180078. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views ...
INTRODUCTION Epidemiological reports have shown an association between heat stroke and increased risk of cardiovascular disease later in life. Using a preclinical model of exertional heat stroke (EHS), we reported metabolic disturbances in the myocardium of female mice that emerge after 9–14 d of recovery. However, it is unknown whether these metabolic changes are accompanied by oxidative stress and inflammation in the myocardium. PURPOSE To determine whether EHS exposure induces oxidative stress and inflammation in the ventricular myocardium during recovery. METHODS Male and female C57BL6 mice underwent surgical implantation of telemetry devices to monitor core temperature, followed by 3 weeks of exercise wheel running, and an EHS trial, consisting of forced wheel running in 37.5°C, 40% humidity. Results were compared to matched exercise controls (EXC), that performed the same exercise at ~22°C and recovered for 4 d. Ventricular samples were collected at 30 min, 3 h, 24 h, 4 d, 9 d and 14 d post EHS for metabolomics testing (n=8/group). Portions of the ventricles from the 14 d time point were also preserved in formalin, sectioned and stained with H&E. The entire cross section of each ventricular section was divided into a grid and each section of the grid graded from 0–3 based on severity of inflammation. RESULTS Female mice exhibited greater heat tolerance but were exposed to much higher durations of exercise and heat load during the EHS protocol, as previously described. Metabolomic analyses determined that the myocardium of females exhibited multiple markers of oxidative stress that were not seen in males. Glutathione levels decreased by ~40% by 4 d and recovered at later timepoints. Oxidized glutathione increased by ~25% at 24 h post EHS and returned to baseline levels in later recovery periods. The oxidation product, 13‐HODE/9‐HODE continued to increase beyond 3 h post EHS, reaching ~400% of EXC (P<0.001) at 14 d. Other markers such as 4‐hydroxy‐nonenal glutathione, methionine sulfone and trimethylamine N‐oxide showed biphasic responses, characterized by a significant elevation at 30 min, a recovery at 3 h, and then large elevations, reaching 200%–400% of EXC. Histological markers of inflammation were also elevated in females in the 14 d EHS hearts compared to EXC (P<0.001). This was not seen in male hearts. CONCLUSIONS Our data suggest that EHS in females, but not males, results in oxidative stress and increased inflammation in the ventricular myocardium during recovery. We speculate that sex differences arose from either the greater heat load experienced by females or by unique sex‐dependent differences in metabolic control. Though the translation of these results to the human condition is highly speculative, it is possible that such EHS‐induced cardiovascular events may comprise an origin of the cardiovascular susceptibilities to disease later in life that have been previously observed in heat stroke victims. Support or Funding Information Supported by DoD Grant W81XWH‐15‐2‐0038 and the BK and Betty Stev...
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