Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs.

Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17β-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague-Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA).

Deficiency in Heat Shock Factor 1 (HSF-1) Expression Exacerbates Sepsis-induced Inflammation and Cardiac Dysfunction.

In the present study, we investigated whether absence of heat shock factor 1 (HSF-1) and inability to increase myocardial expression of heat shock proteins alter septic responses of inflammatory cytokines and myocardial contractility. HSF-1 knockout ( ) mice and wild type litter mates underwent a sterile (lipopolysaccharide; LPS) or infectious ( or septic challenge. Production of cytokines, TNF, IL-1β, IL-6 and IL-10, in the blood and from cardiomyocytes was exaggerated in the mice compared to responses measured in wild type mice given an identical septic challenge.

17β-Estradiol reappropriates mass lost to the hypermetabolic state in thermally injured rats.

Background: The hypermetabolic response to severe thermal injury is unlike any physiologic response seen in medicine. While some parallels can be drawn to shock and sepsis states, this response is typified by its intensity and duration. Our group has been interested in the myriad effects of estrogens after injury, specifically the ability of estrogens to reduce inflammatory responses.

Sepsis-induced cardiac mitochondrial dysfunction involves altered mitochondrial-localization of tyrosine kinase Src and tyrosine phosphatase SHP2.

Our previous research demonstrated that sepsis produces mitochondrial dysfunction with increased mitochondrial oxidative stress in the heart. The present study investigated the role of mitochondria-localized signaling molecules, tyrosine kinase Src and tyrosine phosphatase SHP2, in sepsis-induced cardiac mitochondrial dysfunction using a rat pneumonia-related sepsis model. SD rats were given an intratracheal injection of Streptococcus pneumoniae, 4×10(6) CFU per rat, (or vehicle for shams); heart tissues were then harvested and subcellular fractions were prepared.

Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model.

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat).

Burn serum causes a CD14-dependent mitochondrial damage in primary cardiomyocytes.

Studies from animal models suggest that myocardial mitochondrial damage contributes to cardiac dysfunction after burn injury. In this report, we used an ex vivo model of primary cardiomyocyte culture to investigate the mechanisms of burn-induced mitochondrial impairment. Briefly, blood serum was collected from Sprague-Dawley (SD) rats subjected to 40% total body surface area burn and added (10% vol/vol) to primary cardiomyocytes prepared from SD rats.

Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling.

Background: Patients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-alpha, IL-1beta, and IL-6 and the protective effects of acute estrogen treatment on these levels.

Age-dependent differences of interleukin-6 activity in cardiac function after burn complicated by sepsis.

Interleukin (IL)-6 is a pleiotropic cytokine that is activated after acute injuries, and plays an important role during aging. We aim to define the role of IL-6 on myocardial dysfunction following a 40% total body surface area burn followed by late (7 days) Streptococcus pneumoniae sepsis (burn plus sepsis) in 2- and 14-month-old wild type and IL-6(-/-) mice. We measured global hemodynamic and cardiac contractile function with left ventricular pressure-volume analysis 24h after sepsis induction, and measured phosphorylated signal transducer and activator of transcription 3 (p-STAT-3), tumor necrosis factor (TNF)-alpha, and IL-1beta in the heart with Western blot analysis.

Molecular or pharmacologic inhibition of the CD14 signaling pathway protects against burn-related myocardial inflammation and dysfunction.

Signaling through toll-like receptor 4 (TLR4) plays an obligate role in burn-related myocardial dysfunction. We hypothesized that signaling through CD14, a cellular receptor for endotoxin that lacks a transmembrane domain but is coupled to TLR4, also plays a role in postburn myocardial inflammation and dysfunction. Burn covering 40% total body surface area (or sham burn for controls) was produced in wild-type (WT) and CD14 knockout (KO) as well as vehicle-treated and geldanamycin-treated WT mice (1 microg/g body weight) to inhibit CD14 signaling.

Increasing percent burn is correlated with increasing inflammation in an adult rodent model.

Burn injury has been associated with systemic/compartmental inflammatory responses and myocardial dysfunction. We hypothesized that burn size correlates with the extent of cardiac inflammatory response/contractile dysfunction. Adult male Sprague-Dawley rats were divided to receive anesthesia, a 3-degree burn covering 20%, 30%, 40%, or 60% total body surface area (TBSA) plus fluid resuscitation (lactated Ringer, 4 mL/kg per percent burn); sham burn animals were included as controls.

Burn injury decreases myocardial Na-K-ATPase activity: role of PKC inhibition.

Cardiomyocyte sodium accumulation after burn injury precedes the development of myocardial contractile dysfunction. The present study examined the effects of burn injury on Na-K-ATPase activity in adult rat hearts after major burn injury and explored the hypothesis that burn-related changes in myocardial Na-K-ATPase activity are PKC dependent. A third-degree burn injury (or sham burn) was given over 40% total body surface area, and rats received lactated Ringer solution (4 ml.

Bactericidal/permeability increasing protein attenuates the myocardial inflammation/dysfunction that occurs with burn complicated by subsequent infection.

Intubation and mechanical ventilation after burn contribute to pneumonia-related infection. Although postburn presence or absence of endotoxin has been described, inactivation of Toll-like receptor 4 signaling has been shown to improve postburn organ function, suggesting that LPS participates in burn-related susceptibility to infection. We hypothesized that bactericidal/permeability-increasing protein (rBPI) given postburn would attenuate myocardial inflammation/dysfunction associated with postburn septic challenge given 7 days postburn.

Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury.

In the heart, thermal injury activates a group of intracellular cysteine proteases known as caspases, which have been suggested to contribute to myocyte inflammation and dyshomeostasis. In this study, Sprague-Dawley rats were given either a third-degree burn over 40% total body surface area plus conventional fluid resuscitation or sham burn injury. Experimental groups included 1) sham burn given vehicle, 400 microl DMSO; 2) sham burn given Q-VD-OPh (6 mg/kg), a highly specific and stable caspase inhibitor, 24 and 1 h prior to sham burn; 3) burn given vehicle, DMSO as above; 4) burn given Q-VD-OPh (6 mg/kg) 24 and 1 h prior to burn.

Cardiac mitochondrial damage and inflammation responses in sepsis.

Background And Purpose: Studies in sepsis suggest that mitochondria mediate multiple organ dysfunction, including cardiac failure; however, the underlying molecular mechanisms remain elusive. This study examined changes in mitochondrial membrane integrity, antioxidant activities, and oxidative stress in the heart after infectious challenge (intratracheal Streptococcus pneumoniae, 4 x 10(6) colony-forming units). Inflammation responses also were examined.

Reducing susceptibility to bacteremia after experimental burn injury: a role for selective decontamination of the digestive tract.

We proposed that selective decontamination of the digestive tract (SDD) initiated after experimental burn injury would decrease myocardial inflammation and dysfunction after a second insult such as septic challenge. Rats were divided into eight experimental groups. Groups included sham burn plus sham sepsis, burn alone, sepsis alone, and burn plus sepsis given either water by oral gavage for 5 days after burn (or sham burn) or given oral antibiotics (polymyxin E, 15 mg; tobramycin, 6 mg; 5-flucytosin, 100 mg given by oral gavage, 2x daily for 5 days after burn or sham burn).

Role of interleukin-6 in cardiac inflammation and dysfunction after burn complicated by sepsis.

To examine the role of myocardial interleukin-6 (IL-6) in myocardial inflammation and dysfunction after burn complicated by sepsis, we performed 40% total body surface area contact burn followed by late (7 days) Streptococcus pneumoniae pneumonia sepsis in wild-type (WT) mice, IL-6 knockout (IL-6 KO) mice, and transgenic mice overexpressing IL-6 in the myocardium (TG). Twenty-four hours after sepsis was induced, isolated cardiomyocytes were harvested and cultured in vitro, and supernatant concentrations of IL-6 and tumor necrosis factor (TNF)-alpha were measured. Cardiomyocyte intracellular calcium ([Ca(2+)](i)) and sodium ([Na(+)](i)) concentrations were also determined.

Sepsis and burn complicated by sepsis alter cardiac transporter expression.

Unlabelled: Sepsis alone and burn complicated by sepsis produce significant cardiac dysfunction. Since calcium handling by the cardiomyocyte is essential for cardiac function, one mechanism for cardiac abnormalities may be calcium dyshomeostasis. We hypothesized that sepsis and burn plus sepsis alter cardiac calcium transporter expression.

The effects of early excision and grafting on myocardial inflammation and function after burn injury.

Background: Sepsis is a frequent complication of burn injury despite absence of confirmed infection. Numerous investigators have proposed that the burn wound itself is a primary stimulus for postburn inflammation, and that early excision of the burn wound attenuates the hypermetabolic and inflammatory responses to burn injury. However, others have suggested that aggressive fluid resuscitation and correction of postburn fluid and electrolyte deficits should be the primary focus of intervention in the first 24 hours postburn.

Effects of burn injury on myocardial signaling and cytokine secretion: Possible role of PKC.

This study examined the effects of major burn injury on the cellular distribution of several PKC isoforms in adult rat hearts and examined the hypothesis that PKC plays a regulatory role in cardiomyocyte cytokine secretion. Burn trauma was given over 40% total body surface area in Sprague-Dawley rats. An in vitro model of burn injury included addition of burn serum, 10% by volume, to primary cardiomyocyte cultures (collagen perfusion).

Cardiac mitochondrial damage and loss of ROS defense after burn injury: the beneficial effects of antioxidant therapy.

Mechanisms of burn-related cardiac dysfunction may involve defects in mitochondria. This study determined 1) whether burn injury alters myocardial mitochondrial integrity and function; and 2) whether an antioxidant vitamin therapy prevented changes in cardiac mitochondrial function after burn. Sprague-Dawley rats were given a 3 degrees burn over 40% total body surface area and fluid resuscitated.

Antioxidant vitamin therapy alters sepsis-related apoptotic myocardial activity and inflammatory responses.

This study examined the effects of antioxidant vitamins on several aspects of sepsis-related myocardial signaling cascades. Sprague-Dawley rats were divided into four groups: group 1, vehicle-treated shams; group 2, sham-operated rats given antioxidant vitamins (vitamin C, 24 mg/kg; vitamin E, 20 U/kg; vitamin A, 417 U/kg; and zinc, 3.7 ng/kg) by oral gavage in 0.

Echocardiography assessment of myocardial function after burn injury.

Introduction: Echocardiography provides noninvasive and clinically relevant assessment of left ventricle (LV) function in injury and disease. In this present study, we hypothesized that application of transthoracic echocardiography in awake mice would provide in vivo assessment of myocardial performance that correlates with in vitro assessment of LV function using isolated perfused hearts (Langendorff).

Methods: Burn over 40% of the total body surface area (or sham burn) was given in C57/BL6 mice 22 to 24 g; lactated Ringer fluid resuscitation was given intraperitoneally.

Nitric oxide donors alter cardiomyocyte cytokine secretion and cardiac function.

Objects: The mechanisms by which nitric oxide produces beneficial/detrimental effects on physiologic function are unclear. In this study, we hypothesized that nitric oxide promotes cyclic guanosine monophosphate (cGMP) formation, which, in turn, promotes cardiomyocyte secretion of inflammatory cytokines as well as accumulation of intracellular Na+/Ca2+; these factors contribute to altered cardiac contractile function.

Design: Laboratory study.

Hypertonic saline dextran after burn injury decreases inflammatory cytokine responses to subsequent pneumonia-related sepsis.

The present study examined the hypothesis that hypertonic saline dextran (HSD), given after an initial insult, attenuates exaggerated inflammation that occurs with a second insult. Adult rats (n = 15 per group) were divided into groups 1 (sham burn), 2 [40% total body surface area burn + 4 ml/kg isotonic saline (IS) + 4 ml.kg(-1).

Murine in vivo myocardial contractile dysfunction after burn injury is exacerbated by pneumonia sepsis.

We evaluated hemodynamic and cardiac contractile dysfunction in a murine model of 40% contact burn complicated by Streptococcus pneumoniae (1 x 10(5) CFU) sepsis. Male, 9- to 10-week-old C57/BL6 mice were divided into the following groups: sham burn, sham sepsis; 24 h after burn alone; 24 h after sepsis alone; 7 days after burn alone; and 7 days after burn followed by pneumonia sepsis. Hemodynamic and cardiac contractile function was assessed with carotid artery cannulation and left ventricular pressure-volume analysis.