RESUMO
Tumor necrosis factor (TNF) is considered an adverse mediator of heat stroke (HS) based on clinical studies showing high serum levels. However, soluble TNF receptors (sTNFR; TNF antagonists) were higher in survivors than nonsurvivors, and TNFR knockout (KO) mice showed a trend toward increased mortality, suggesting TNF has protective actions for recovery. We delineated TNF actions in HS by comparing thermoregulatory, metabolic, and inflammatory responses between B6129F2 (wild type, WT) and TNFR KO mice. Before heat exposure, TNFR KO mice showed ~0.4°C lower core temperature (T(c); radiotelemetry), ~10% lower metabolic rate (M(r); indirect calorimetry), and reduced plasma interleukin (IL)-1α and sIL-1RI than WT mice. KO mice selected warmer temperatures than WT mice in a gradient but remained hypothermic. In the calorimeter, both genotypes showed a similar heating rate, but TNFR KO maintained lower T(c) and M(r) than WT mice for a given heat exposure duration and required ~30 min longer to reach maximum T(c) (42.4°C). Plasma IL-6 increased at ~3 h of recovery in both genotypes, but KO mice showed a more robust sIL-6R response. Higher sIL-6R in the KO mice was associated with delayed liver p-STAT3 protein expression and attenuated serum amyloid A3 (SAA3) gene expression, suggesting the acute phase response (APR) was attenuated in these mice. Our data suggest that the absence of TNF signaling induced a regulated hypothermic state in the KO mice, TNF-IL-1 interactions may modulate T(c) and M(r) during homeostatic conditions, and TNF modulates the APR during HS recovery through interactions with the liver IL-6-STAT3 pathway of SAA3 regulation.
Assuntos
Proteínas de Fase Aguda/metabolismo , Regulação da Temperatura Corporal/fisiologia , Golpe de Calor/metabolismo , Golpe de Calor/fisiopatologia , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/genética , Animais , Metabolismo Basal/fisiologia , Temperatura Corporal/fisiologia , Modelos Animais de Doenças , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Radiotelemetry transmitters support tracking of physiologic variables in conscious animals, but the size of the transmitter may alter animal health and behavior. We hypothesized that the size of the device adversely affects body weight, food intake, water intake, circadian core temperature, activity, voluntary running patterns, and the health of internal organs and that these negative effects can be minimized with smaller transmitter devices. Male C57BL/6J mice (weight, 20 to 24 g) were implanted with small (1.1 g, 0.52 mL) or large (3.5 g, 1.75 mL) radiotransmitters. Recovery of presurgical body weight, food intake, and water intake occurred within 3 d in mice implanted with small transmitter and 9 d in those with large transmitters. Mice with small transmitters displayed robust circadian core body temperature and activity patterns within 1 d after surgery, whereas activity was depressed in mice with large transmitters throughout experimentation. The most robust effects of the large transmitter included significantly reduced voluntary running, which never recovered to baseline, and inflammation of the diaphragm, large intestine, and duodenum. These results demonstrate that the large transmitter delayed surgical recovery, disrupted normal growth, reduced voluntary running, and induced inflammatory reactions of the internal organs of mice. The choice of radiotelemetry transmitter can significantly affect the health and wellbeing of experimental mice as well as data quality, such that the smallest transmitter device available and appropriate to the situation should be chosen for experimentation.
Assuntos
Camundongos Endogâmicos C57BL/fisiologia , Atividade Motora/fisiologia , Telemetria/instrumentação , Animais , Temperatura Corporal , Peso Corporal , Diafragma/patologia , Ingestão de Líquidos , Duodeno/patologia , Ingestão de Alimentos , Intestino Grosso/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL/cirurgia , Distribuição Aleatória , Corrida/fisiologia , Telemetria/métodosRESUMO
Buprenorphine (Bup) is the most commonly used analgesic in mice, yet few objective assessments address its superiority for postsurgical recovery. In mice, IP implantation of a radiotelemetry device induces decreases in body weight (BW), food and water intake (FI, WI), core temperature (Tc), and activity levels that persist approximately 14 d in the absence of analgesia. To compare the efficacy of Bup with that of the nonsteroidal antiinflammatory drug indomethacin (Indo) for postsurgical recovery, male C57BL/6J mice were treated on the day of radiotelemetry implantation with Bup (0.3 mg/kg s.c.) or Indo (1 mg/kg s.c.) followed by treatment with Indo (1 mg/kg p.o.) on the next day (Bup-Indo versus Indo-Indo). Responses were compared between treatments in mice implanted with a radiotelemetry device and those that did not undergo surgery. Changes in BW, FI, WI, Tc, and activity were examined throughout 14 d of recovery. Indo-Indo was more efficacious in inhibiting postsurgical BW, FI, and WI reductions, compared with Bup-Indo. Bup also reduced BW and FI in the absence of surgery, indicating a nonspecific effect of this drug on these variables. Indo-Indo treatment was associated with higher activity levels during lights-on-to-lights-off transition periods compared with that observed with Bup-Indo. According to 5 objective measures of surgical recovery, our data suggest that Indo-Indo treatment is more efficacious than is Bup-Indo for postsurgical recovery of radiotelemetry-implanted mice.
Assuntos
Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Buprenorfina/uso terapêutico , Indometacina/uso terapêutico , Dor Pós-Operatória/prevenção & controle , Administração Oral , Animais , Peso Corporal/fisiologia , Ingestão de Líquidos/fisiologia , Quimioterapia Combinada , Ingestão de Alimentos/fisiologia , Ciência dos Animais de Laboratório/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Dor Pós-Operatória/fisiopatologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Organismos Livres de Patógenos Específicos , TelemetriaRESUMO
Elevated circulating cytokines are observed in heatstroke patients, suggesting a role for these substances in the pathophysiological responses of this syndrome. Typically, cytokines are determined at end-stage heatstroke such that changes throughout progression of the syndrome are poorly understood. We hypothesized that the cytokine milieu changes during heatstroke progression, correlating with thermoregulatory, hemodynamic, and tissue injury responses to heat exposure in the mouse. We determined plasma IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IFN-gamma, macrophage inflammatory protein-1alpha, TNF-alpha, corticosterone, glucose, hematocrit, and tissue injury during 24 h of recovery. Mice were exposed to ambient temperature of 39.5 +/- 0.2 degrees C, without food and water, until maximum core temperature (T(c,Max)) of 42.7 degrees C was attained. During recovery, mice displayed hypothermia (29.3 +/- 0.4 degrees C) and a feverlike elevation at 24 h (control = 36.2 +/- 0.3 degrees C vs. heat stressed = 37.8 +/- 0.3 degrees C). Dehydration ( approximately 10%) and hypoglycemia ( approximately 65-75% reduction) occurred from T(c,Max) to hypothermia. IL-1alpha, IL-2, IL-4, IL-12p70, IFN-gamma, TNF-alpha, and macrophage inflammatory protein-1alpha were undetectable. IL-12p40 was elevated at T(c,Max), whereas IL-1beta, IL-6, and IL-10 inversely correlated with core temperature, showing maximum production at hypothermia. IL-6 was elevated, whereas IL-12p40 levels were decreased below baseline at 24 h. Corticosterone positively correlated with IL-6, increasing from T(c,Max) to hypothermia, with recovery to baseline by 24 h. Tissue lesions were observed in duodenum, spleen, and kidney at T(c,Max), hypothermia, and 24 h, respectively. These data suggest that the cytokine milieu changes during heat strain recovery with similarities between findings in mice and those described for human heatstroke, supporting the application of our model to the study of cytokine responses in vivo.