Biomedical subjects

I H Chaudry

Publications and source records attributed to I H Chaudry.

At least 55 records · Page 3Linked to original sources

PubMed2000

Immune dysfunction following trauma-haemorrhage: influence of gender and age.

Recent studies indicate that young female proestrus mice show an enhanced immune response following trauma-haemorrhage, as opposed to the immunodepression observed in males of comparable age. Testosterone is suggested as the cause of immunodepression in males, whereas oestradiol seems to be responsible for the enhanced immune response in females, however, sex hormone levels decrease with age. To determine if the sexual dimorphism in immune responses observed in young mice following trauma-haemorrhage changes with age, young (2-3 months) and aged (18-19 months) male and female CBA/J NIA mice were subjected to soft-tissue trauma (laparatomy) and haemorrhage (35+5 mmHg for 90 min and fluid resuscitation) or sham operation. Mice were killed 24 h later, and whole blood, as well as splenic and peritoneal macrophages (Mstraight phi) obtained. Plasma 17beta-oestradiol and free testosterone decreased in aged females and males, respectively. Mstraight phi from young females had enhanced IL-1beta and suppressed IL-10 production following trauma-haemorrhage, while aged females had unchanged production IL-1beta and IL-6 production and enhanced IL-10 release. In contrast, IL-1beta and IL-6 production by Mbeta from young males was suppressed and IL-10 production enhanced following trauma-haemorrhage, whereas Mstraight phi from aged males produced elevated levels of IL-1beta and IL-6 and suppressed levels of IL-10 following trauma-haemorrhage. Thus, the gender-related changes in the immune response to trauma-haemorrhage were reversed in aged mice.

Age Factors↗

PubMed2000

The important role of the gut in initiating the hyperdynamic response during early sepsis.

BACKGROUND: Although the initial response to sepsis includes a hyperdynamic phase and although the increased hepatic perfusion in early sepsis is due solely to the increased portal blood flow, it remains unknown whether the gut plays an important role in producing such a response. MATERIALS AND METHODS: Adult male Sprague-Dawley rats underwent a complete enterectomy (ER) before being subjected to sepsis by cecal ligation and puncture (CLP; the cecum was excised from the removed gut and stitched to the posterior peritoneum in ER groups) or sham operation. At 2 h after CLP (i.e., the early, hyperdynamic phase of sepsis), cardiac output and heart performance (+/-dP/dt(max)), as well as hepatic and renal blood flow, were measured. Systemic and regional oxygen delivery (DO(2)) and oxygen consumption (VO(2)) were also determined. RESULTS: Cardiac output, heart performance, organ blood flow, as well as DO(2) and VO(2), increased significantly 2 h after CLP. ER prior to the onset of sepsis, however, prevented the elevation of those parameters. ER in sham animals did not alter the measured parameters with the exception that portal blood flow decreased by 85% and hepatic arterial blood flow increased by 368%, resulting in no significant reduction in hepatic DO(2) and VO(2). There were no changes in circulating blood volume among groups, indicating that the effect of ER on hemodynamics after CLP was not due to alterations in blood volume. CONCLUSION: Since ER immediately before the onset of sepsis prevents the increase in cardiac output and regional hemodynamics, the gut appears to play an important role in producing the hyperdynamic response during the early stage of polymicrobial sepsis.

Animals↗

PubMed2000

IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis.

BACKGROUND: Although studies have shown that there is a marked depression in cell-mediated (T(H)(1)) immunity after the onset of sepsis, the mechanism by which this occurs remains unknown. In this regard, the T(H2) cytokine IL-4 is known to regulate T(H1) and T(H2) cell responsiveness primarily through the activation of the signal transducer and activation of transcription factor-6 (Stat6) pathway. METHODS: We hypothesized that IL-4 may contribute to the suppression of cell-mediated immunity and to death seen in sepsis and that IL-4 may be acting through the Stat6 pathway. To determine this, we induced cecal ligation and puncture (CLP) or sham-CLP in male BALB/c mice. Mice received 2 mg of monoclonal antibody against IL-4 or IgG control at 12 hours after CLP (ie, at the onset of immune suppression). Splenic T cells were then isolated 24 hours after CLP and stimulated with monoclonal antibody to CD3. Cytokine release and Stat6 phosphorylation (activation) were determined. In a separate group of animals, survival was assessed over 10 days. RESULTS: The results indicate that after CLP, T cells are suppressed in their ability to release the T(H1) cytokines, IL-2 and IFN-gamma. Alternatively, the release of T(H2) cytokines IL-10 and IL-4 is markedly increased after CLP. This was associated with an increase in phosphorylated Stat6 protein. In vivo treatment of mice with monoclonal antibody to IL-4 at 12 hours after CLP restores T(H1) responsiveness while preventing the increase in T(H2) cytokine release and Stat6 phosphorylation. Furthermore, neutralization of IL-4 markedly increased the survival rates in septic animals. CONCLUSIONS: Taken together, these data indicate that the T(H2) cytokine IL-4 contributes to the suppression of cell-mediated immunity and death associated with polymicrobial sepsis and suggest that IL-4 may be acting through the Stat6 pathway in septic animals.

Animals↗

PubMed2000

Insight into the mechanism by which estradiol improves organ functions after trauma-hemorrhage.

BACKGROUND: Recent studies have indicated that female rodents with high levels of estradiol (proestrus) have better organ functions after trauma-hemorrhage than females with low estradiol levels (estrus) or male animals. However, the precise role of estrogens in maintaining organ function after hemorrhage remains unknown. METHODS: Adult female Sprague-Dawley rats were ovariectomized 14 days before the experiment to decrease circulating levels of estradiol. Animals underwent laparotomy to induce tissue trauma and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer's lactate. Resuscitation was carried out with 4 times the volume of maximal bleed-out with Ringer's lactate during a period of 1 hour. 17beta-Estradiol (E2, 1 mg/kg body weight intravenously) with or without a specific estrogen receptor antagonist ICI 182,780 (3 mg/kg body weight intraperitoneally) was given at the beginning of resuscitation. At 24 hours after hemorrhage and resuscitation, cardiovascular and hepatocellular functions (ie, the maximal velocity and overall efficiency of indocyanine green clearance) were determined. Plasma E2 was also assayed. The effects of ovariectomy and E2 administration on uterine weight were measured in additional groups of animals. RESULTS: The results indicate that cardiovascular and hepatocellular organ functions were significantly depressed after trauma-hemorrhage and were restored in animals receiving E2. However, simultaneous administration of its specific receptor antagonist abolished the salutary effects of E2 treatment despite high circulating levels of E2. Uterine weight decreased at 14 days after ovariectomy, which was partially restored with a single dose of E2. CONCLUSIONS: Administration of 17beta-estradiol should be considered a novel and safe adjunct for ameliorating hemorrhage-induced organ dysfunctions in ovariectomized and postmenopausal women because of their low estradiol levels.

Animals↗

PubMed2000

Inhibition of tyrosine kinase signaling after trauma-hemorrhage: a novel approach for improving organ function and decreasing susceptibility to subsequent sepsis.

OBJECTIVE: To determine whether administration of a tyrosine kinase inhibitor after trauma-hemorrhage has any beneficial effects on cardiovascular parameters and hepatocellular function and on survival rate after subsequent sepsis. BACKGROUND: Increased inflammatory cytokine release and concomitant activation of intracellular signaling pathways contributes to multiple organ dysfunction and increased susceptibility to subsequent sepsis after severe hemorrhagic shock. METHODS: Male Sprague-Dawley rats underwent a midline laparotomy (i.e., soft-tissue trauma induced) and were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer's lactate. The rats were then resuscitated with four times the shed blood volume in the form of Ringer's lactate during a 60-minute period. A tyrosine kinase inhibitor, AG 556 (7.5 mg/kg), or vehicle was administered intraperitoneally at the middle of resuscitation. At 24 hours after resuscitation, various in vivo parameters such as heart performance, cardiac index, and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined. Phosphorylation state of the mitogen-activated protein kinases p44/42 and p38 in the liver was assessed by Western blot analysis. In additional groups of rats, sepsis was induced by cecal ligation and puncture at 20 hours after hemorrhage. The necrotic cecum was excised 10 hours thereafter, and the survival rate was monitored for a period of 10 days. RESULTS: AG 556 treatment restored the depressed cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation, which was associated with reduced phosphorylation of mitogen-activated protein kinases p44/42 and p38. Moreover, treatment with AG 556 significantly increased the survival rate of rats after trauma-hemorrhage and induction of subsequent sepsis compared with vehicle-treated rats. CONCLUSION: Inhibition of tyrosine kinase signaling after trauma-hemorrhage may represent a novel therapeutic approach for improving organ functions and decreasing the death rate from subsequent sepsis under such conditions.

Animals↗

PubMed2000

Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals.

OBJECTIVE: To determine whether female sex steroids have any salutary effects on the depressed cardiovascular and hepatocellular functions following trauma and hemorrhage in male animals. SUMMARY BACKGROUND DATA: Studies indicate that gender difference exists in the immune and cardiovascular responses to trauma-hemorrhage, and that male sex steroids appear to be responsible for producing immune and organ dysfunction, but it remains unknown if female sex steroids produce any salutary effects on the depressed cellular and organ functions in males following trauma and hemorrhage. METHOD: Adult male Sprague-Dawley rats underwent a midline laparotomy (i.e., trauma induction), and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximum bleed-out volume was returned in the form of Ringer's lactate (RL). Animals were then resuscitated with RL at 4 times the shed blood over 60 minutes. 17beta-estradiol (50 microg/kg) or an equal volume of vehicle was injected subcutaneously 15 minutes before the end of resuscitation. The maximal rate of ventricular pressure increase or decrease (+/-dP/dtmax), cardiac output, and hepatocellular function (i.e., maximal velocity and overall efficiency of in vivo indocyanine green clearance) were assessed at 24 hours after hemorrhage and resuscitation. Plasma levels of interleukin (IL)-6 were also measured. RESULTS: Left ventricular performance, cardiac output, and hepatocellular function decreased significantly at 24 hours after trauma-hemorrhage and resuscitation. Plasma levels of IL-6 were elevated. Administration of 17beta-estradiol significantly improved cardiac performance, cardiac output, and hepatocellular function, and attenuated the increase in plasma IL-6 levels. CONCLUSION: Administration of estrogen appears to be a useful adjunct for restoring cardiovascular and hepatocellular functions after trauma-hemorrhage in male rats.

Analysis of Variance↗

PubMed2000

Effect of naloxone on immune responses after hemorrhagic shock.

OBJECTIVE: To determine whether naloxone administration after hemorrhagic shock has any beneficial or deleterious effect on immune responses. BACKGROUND DATA: Hemorrhagic shock is known to produce immunodepression in both humans and experimental animals. Although studies suggest that endogenous opioids play a role in immune regulation in adverse circulatory conditions, it remains controversial whether these opioids exert beneficial or detrimental effects on immunity after shock. Moreover, little information is available concerning the effects of opioid receptor blockade using naloxone on cell-mediated immunity and endocrine responses after shock. METHODS: Male C3H/HeN mice (25 g) were bled to and maintained at a mean arterial blood pressure of 35+/-5 mm Hg for 1 hr. The shed blood was then returned along with lactated Ringer's solution (two times the shed blood volume) to provide fluid resuscitation. The animals were randomized to receive either naloxone (1 mg/kg i.v.) or an equal volume of vehicle (saline) after the shed blood was returned, i.e., immediately before crystalloid resuscitation, and were killed at 2 hrs after resuscitation to obtain splenocytes, macrophages (peritoneal and splenic), and blood. MEASUREMENTS AND MAIN RESULTS: Bioassays revealed significantly decreased release of all studied interleukins (interleukins-1, -2, -3, and -6) by peritoneal and splenic macrophages as well as significantly decreased splenocyte proliferative capacity after shock in vehicle-treated mice. Naloxone administration after hemorrhage resulted in either similar or even more decreased levels of interleukin release compared with vehicle-treated hemorrhaged mice. Significantly increased plasma corticosterone concentrations were observed in vehicle-treated animals compared with control animals. Naloxone administration did not have any significant effects on corticosterone plasma concentrations after hemorrhage. CONCLUSIONS: These findings indicate the importance of the endogenous opioid system for the maintenance of immunity in adverse circulatory conditions, i.e., hemorrhage. Although additional studies involving different doses and/or times of naloxone administration may provide different results, the present findings raise the concern that naloxone administration in the traumatized host may have deleterious effects because it decreases peritoneal macrophage and splenic immune functions.

Animals↗

PubMed2000

Is prostacyclin responsible for producing the hyperdynamic response during early sepsis?

OBJECTIVE: Although polymicrobial sepsis is characterized by an early hyperdynamic phase (2-10 hrs after cecal ligation and puncture [CLP]), followed by a late hypodynamic phase (20 hrs after CLP), it remains unknown whether prostacyclin or prostaglandin I2 (PGI2) plays a significant role in modulating the hyperdynamic state during early sepsis. The aim of this study was to determine whether inhibition of PGI2 synthesis prevents the occurrence of the hyperdynamic response during early sepsis. DESIGN: Prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: Adult male Sprague-Dawley rats were subjected to sepsis by CLP. INTERVENTIONS AND MEASUREMENTS: Blood samples were collected at 2, 5, 10, or 20 hrs after CLP, and plasma concentrations of PGI2, in the form of its stable product 6-keto-PGF1alpha, were measured by radioimmunoassay. In additional studies, a PGI2 synthase inhibitor, tranylcypromine, was administered subcutaneously at the time of CLP and again at 3 hrs after CLP. At 5 hrs after the onset of sepsis, the maximal rates of the left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax) were determined by an in vivo heart performance analyzer. Microvascular blood flow in the liver, small intestine, and spleen was assessed by laser Doppler flowmetry. MAIN RESULTS: Plasma concentrations of 6-keto-PGF1alpha increased significantly at 2-20 hrs after CLP. At 5 hrs after the onset of sepsis, +/-dP/dt(max) and microvascular blood flow in the tested tissues increased significantly. Inhibition of PGI2 synthase activity did not prevent the occurrence of hypercardiovascular responses under such conditions. Moreover, the administration of tranylcypromine significantly reduced circulating concentrations of 6-keto-PGF1alpha at 5 hrs after CLP. CONCLUSIONS: Because inhibition of PGI2 production did not prevent the occurrence of the hyperdynamic and hypercardiovascular response during the early stage of sepsis, mediators other than PGI2 appear to play a major role in producing the hyperdynamic response under such conditions.

6-Ketoprostaglandin F1 alpha↗

PubMed2000

Alterations in tissue oxygen consumption and extraction after trauma and hemorrhagic shock.

OBJECTIVES: Although trauma and hemorrhage are associated with tissue hypoperfusion and hypoxemia, changes in oxygen delivery (DO2), oxygen consumption VO2), and oxygen extraction at the organ level in a small animal (such as the rat) model of trauma and hemorrhage have not been examined. Therefore, the objectives of this study were to determine whether blood flow, DO2, VO2, and oxygen extraction ratio in various organs are differentially altered after trauma-hemorrhagic shock and acute resuscitation in the rat. DESIGN: Prospective, randomized animal study. SETTING: A university research laboratory. SUBJECTS: Male Sprague-Dawley rats (n = 6-7 animals/group) weighing 275-325 g. INTERVENTIONS: Male rats underwent laparotomy (i.e., soft tissue trauma) and were bled to and maintained at a blood pressure of 40 mm Hg until 40% of shed blood volume was returned in the form of lactated Ringer's solution. They were then resuscitated with four times the volume of shed blood with lactated Ringer's solution for 60 mins. At 1.5 hrs postresuscitation, cardiac output and blood flow were determined by using strontium-85 microspheres. Blood samples (0.15 mL each) were collected from the femoral artery and vein and the hepatic, portal, and renal veins to determine total hemoglobin and oxygen content. Systemic and regional DO2, VO2, and oxygen extraction ratio were then calculated. MEASUREMENTS AND MAIN RESULTS: Both the systemic hemoglobin and systemic arterial oxygen content in hemorrhaged animals at 1.5 hrs postresuscitation were >50% lower as compared with sham-operated controls. Cardiac output and blood flow in the liver, small intestine, and kidneys decreased significantly, but blood flow in the brain and heart remained unaltered after hemorrhage and resuscitation. Systemic DO2 and VO2 were 73% and 54% lower, respectively, than controls at 1.5 hrs after resuscitation. Similarly, regional DO2 and VO2 in the liver, small intestine, and kidneys decreased significantly under such conditions. In addition, the liver had the most severe reduction in VO2 (76%) among the tested organs. However, the oxygen extraction ratio in the liver of sham animals was the highest (72%) and remained unchanged after hemorrhage and resuscitation. CONCLUSION: Because the liver experienced the most severe reduction in VO2 associated with an unchanged oxygen extraction capacity, this organ appears to be more vulnerable to hypoxic insult after hemorrhagic shock.

Animals↗

PubMed2000

Immune depression in polymicrobial sepsis: the role of necrotic (injured) tissue and endotoxin.

OBJECTIVE: Recent studies suggest immune dysfunction seen after the onset of polymicrobial sepsis, as produced by cecal ligation and puncture (CLP), is not caused by endotoxin (ETX) alone, but may be caused by the combined effect of the necrotic tissue (cecal ligation, [CL]) and other microbial components. Thus, the objective of this study was to assess the ability of necrotic tissue, in the presence or absence of low-dose endotoxin, to induce changes in the capacity of immune cells to produce proinflammatory or anti-inflammatory cytokines approximating those seen in CLP. DESIGN: Experimental, prospective study. SETTING: A hospital laboratory in the Center for Surgical Research. SUBJECTS: Male C3H/HeN mice. INTERVENTIONS: Mice were subjected to a CL and saline infusion (CL/Sal), CL in combination with low-dose ETX infusion (CL/ETX) (0.025 mg ETX/25 g body weight/24 hrs by a peritoneally implanted osmotic mini-pump), ETX infusion alone, saline infusion alone (Sal), CLP, or sham-CLP (Sham). Splenocytes, splenic macrophage and peritoneal macrophage were harvested from these animals 24 hrs (late) after being subjected to the above protocols. Splenocyte and macrophage inducible cytokine release was assessed by ELISA/bioassay. Survival over a 7-day period was also examined in additional groups. MEASUREMENTS AND MAIN RESULTS: Our results indicate a marked decrease in splenic interleukin (IL)-2. In addition, peritoneal or splenic macrophage IL-6 productive capacity was depressed in cells from animals subjected to CL/ETX or CLP. Alternatively, CL, in the presence or absence of ETX, induced a marked change in macrophage cytokine release capacity comparable to that seen in CLP, ie, decreased IL-12 release and increased IL-10 secretion. To the extent these cellular alterations contribute to an increase in mortality rate, we observed in subsequent survival studies that neither CL alone nor ETX produced mortality. However, the combination of CL/ETX markedly increased 7-day mortality rate (approximately 33%), although not to the same extent as CLP (80%). CONCLUSIONS: These results collectively suggest that the response to devitalized tissue produced by cecal ligation may predispose the host to the induction of a suppressive macrophage phenotype. The subsequent exposure of these animals to microbial agents induces immune dysfunction, as well as mortality seen after such a polymicrobial septic challenge.

Animals↗

PubMed2000

L-arginine attenuates trauma-hemorrhage-induced liver injury.

OBJECTIVES: Liver injury is common after trauma-hemorrhage for which the underlying mechanism is not clear. Although administration of the essential amino acid L-arginine has been reported to restore the depressed cardiovascular functions and cell-mediated immune responses after trauma-hemorrhage, it remains unknown whether L-arginine protects against liver injury under those conditions. DESIGN: A prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats underwent sham operation or laparotomy and were bled to and maintained at a mean arterial blood pressure of 40 mm Hg until 40% of the maximum shed blood volume was returned in the form of lactated Ringer's solution. Hemorrhaged rats were then resuscitated with lactated Ringer's solution, four times the maximum shed blood volume over 1 hr. During resuscitation, animals received either 300 mg/kg of L-arginine or saline (vehicle) intravenously. At 3 and 5 hrs after resuscitation, rats were killed, blood was obtained, and the liver was fixed for histology (hematoxylin & eosin staining). Plasma glutathione S-transferase (a marker of liver damage), L-arginine, citrulline, and ornithine concentrations were assessed. MEASUREMENTS AND MAIN RESULTS: The increased concentrations of plasma glutathione S-transferase observed in vehicle-treated hemorrhage animals were normalized with L-arginine treatment at 5 hrs after resuscitation. Moreover, the histology indicated that L-arginine prevented liver edema and neutrophil infiltration after trauma-hemorrhage. Plasma L-arginine and citrulline were increased in L-arginine-treated rats. CONCLUSIONS: Because citrulline is a by-product of nitric oxide generation by nitric oxide synthase from L-arginine, this amino acid may be a useful adjunct for preventing hepatic injury after trauma-hemorrhage via endothelial derived nitric oxide production.

Animals↗

PubMed2000

Does early infusion of red blood cells after trauma and hemorrhage improve organ functions?

OBJECTIVE: Early management of trauma victims includes control of bleeding and rapid restoration of intravascular volume. However, it remains controversial whether infusion of blood products is superior to crystalloids alone. Therefore, it was the aim of the present study to determine whether resuscitation with red blood cells plus lactated Ringer's solution (RL) is more effective than RL alone in improving the cardiovascular and hepatocellular functions after trauma and severe hemorrhage. DESIGN: Prospective study. SETTING: Laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS AND MEASUREMENTS: Male adult rats were anesthetized and underwent a laparotomy to induce tissue trauma before hemorrhage. The animals were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out (MB) volume was returned in the form of RL, and were then resuscitated with either four times the volume of MB with RL or washed red blood cells (RBC) (-45% the volume of MB) in three times the volume of RL over 60 mins. Various in vivo heart performance variables, cardiac output, and hepatocellular function (ie, the maximum velocity and the overall efficiency of indocyanine green clearance) were determined at 4 hrs after resuscitation. Hemoglobin, systemic oxygen delivery, circulating blood volume, and plasma levels of interleukin-6 were also measured. MAIN RESULTS: At 4 hrs after RL resuscitation, heart performance, cardiac output and hepatocellular function were significantly depressed and plasma levels of interleukin-6 were significantly increased. Although infusion of RBC significantly increased mean arterial pressure, hemoglobin, and oxygen delivery compared with animals resuscitated with RL only, infusion of RBC did not further improve the depressed cardiovascular and hepatocellular functions under such conditions. CONCLUSION: Because infusion of RBC and RL resuscitation do not improve organ functions compared with RL resuscitation without RBC, it appears that pharmacologic agents in addition to fluid resuscitation are needed to restore cardiovascular and hepatocellular functions after trauma and hemorrhage.

Animals↗

PubMed2000

Should normothermia be restored and maintained during resuscitation after trauma and hemorrhage?

BACKGROUND: Although hypothermia often occurs after trauma and has protective effects during ischemia and organ preservation, it remains unknown whether maintenance of hypothermia or restoring the body temperature to normothermia during resuscitation has any deleterious or beneficial effects on heart performance and organ blood flow after trauma-hemorrhage. METHODS: Male rats underwent laparotomy (i.e., induced trauma) and were exsanguinated to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum shed volume was returned in the form of Ringer's lactate. Body temperature decreased from approximately 36.5 degrees C to below 32 degrees C. The animals were then resuscitated with four times the volume of maximal bleedout with Ringer's lactate. In one group, body temperature was rewarmed to 37 degrees C during resuscitation. In another group, body temperature was maintained at hypothermia (32 degrees C) for 4 hours after resuscitation. In an additional group, the body temperature was kept at 37 degrees C during hemorrhage as well as during resuscitation. Left ventricle performance parameters such as maximal rate of left ventricular pressure increase and decrease (+/-dP/dt(max)) were measured up to 4 hours. Cardiac output and regional blood flow were determined by radioactive microspheres at 4 hours after the completion of resuscitation. RESULTS: The maintenance of normothermia during hemor. rhage or prolonged hypothermia after resuscitation depressed the left ventricular performance parameters, cardiac output, and regional blood flow in various organs. Rewarming the body to normothermia during resuscitation, however, significantly increased heart performance, cardiac output (from hypothermia 16.2 +/- 1.4 to 22.3 +/- 1.4 mL/min per 100 g body weight,p < 0.05) and total hepatic blood flow (from hypothermia 117.5 +/- 5.3 to 166.0 +/- 9.3 mL/min per 100 g tissue, p < .05). CONCLUSION: Our data indicate that restoration of normothermia during resuscitation improves cardiac function and hepatic blood flow compared with hypothermia.

Animals↗

PubMed2000

Septic mucosal intraepithelial lymphoid immune suppression: role for nitric oxide not interleukin-10 or transforming growth factor-beta.

OBJECTIVE: Recent studies indicate that sepsis induces a marked depression in the splenocyte immune response (as illustrated by decreased interleukin [IL]-2 production, interferon [IFN]-gamma production, or both) in response to T-cell mitogen. However, it is not known whether a similar depression is evident in the phenotypically distinct, small intestine intraepithelial lymphocytes (IELs) or what regulates this process during sepsis. Because the maintenance of a competent mucosal immune response is thought to be central to the animal's ability to survive sepsis, we attempted to determine whether IEL's IL-2/IFN-gamma production is suppressed and what mediates this depression. RESULTS: Our studies indicated that C3H/HeN mice subjected to cecal ligation and puncture (CLP) exhibited a marked decline in the ability of IELs to release IL-2/IFN-gamma at 24 hours and that this decline is associated with increased secretion of IL-10 and nitric oxide (NO). To the extent that IL-10 accounted for this loss of IL-2/IFN-gamma release, we observed that IL-10 gene deficiency neither restored the IL-2/IFN-gamma release nor suppressed the increase in NO when compared with background control, C57BL/6J mouse cells. To further study whether NO was involved in this immune suppression, iNOS knockout (iNOS -/-) were also subjected to the same procedure; however, the depression in IL-2/IFN-gamma was not seen in iNOS -/- mice when compared with background controls. CONCLUSION: Our data indicate that IL-10, which affects splenic lymphoid response, may not be a key mediator of IEL immune suppression and that the induction of NO may play a more significant role in gastrointestinal immune dysfunction seen in late sepsis.

Animals↗

PubMed2000

Critical role of oxygen radicals in the initiation of hepatic depression after trauma hemorrhage.

BACKGROUND: Although depression in hepatocellular function occurs early after trauma and severe hemorrhage and persists despite fluid resuscitation, it remains unknown whether reactive oxygen species (ROS) play any role in the initiation of hepatocellular depression and damage under those conditions. We hypothesized that administration of a ROS scavenger at the beginning of resuscitation will attenuate organ injury after severe shock. METHODS: Male Sprague-Dawley rats (275-325 g) underwent laparotomy (i.e., induction of soft tissue trauma) and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of maximal bleed-out with RL over 60 minutes. The ROS scavenger 2-mercaptopropionyl glycine (30 mg/kg) or vehicle was administered intravenously as a bolus at the beginning of resuscitation. At 2 hours after the completion of crystalloid resuscitation or the equivalent interval after sham-operation, cardiac index was measured by a dye dilution technique. Hepatocellular function, i.e., the maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the active transport (Km), was determined using an in vivo hemoreflectometer. Serum levels of tumor necrosis factor (TNF)-alpha and alanine aminotransferase were determined with ELISA and colorimetrically, respectively. RESULTS: The results indicate that at 2 hours after trauma hemorrhage and resuscitation, cardiac index and hepatocellular function were markedly depressed with concomitantly increased serum levels of TNF-alpha and alanine aminotransferase (p < 0.05). Administration of 2-mercaptopropionyl glycine, however, restored the depressed cardiac and hepatic function and markedly attenuated liver enzyme release and serum levels of TNF-alpha (p < 0.05). CONCLUSION: Our data suggest that ROS play a role in producing the depression in organ functions after severe hemorrhagic shock. Thus, adjuncts that attenuate the detrimental effects of ROS may be useful for improving the depressed cardiac and hepatocellular functions after trauma hemorrhage and resuscitation.

Alanine Transaminase↗

PubMed2000

Upregulation of inducible nitric oxide synthase and nitric oxide occurs later than the onset of the hyperdynamic response during sepsis.

Polymicrobial sepsis is characterized by an early, hyperdynamic phase (i.e., 2-10 h after cecal ligation and puncture [CLP]) followed by a late, hypodynamic phase (16 h after CLP or later). Although nitric oxide (NO) plays an important role in the pathophysiologic response during sepsis, it remains unknown how early NO is upregulated after the onset of sepsis and which organs are responsible for producing the increased amount of NO. To study this, male rats were subjected to sepsis by CLP followed by fluid resuscitation. Blood samples were then taken at 2, 5, 10, or 20 h after CLP or sham operation. In additional groups of animals, the kidneys, small intestine, heart, liver, and lungs were harvested at 5 or 10 h after CLP. Plasma and tissue levels of nitrate and nitrite (NO3-/NO2-, stable products of NO) were determined by using a colorimetric assay. Inducible NO synthase (iNOS) mRNA was examined in various tissues harvested at 10 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR) technique. The results indicate that plasma levels of NO3-/NO2- (mainly reflecting iNOS activity) did not increase at 2-5 h but were significantly elevated at 10-20 h after CLP. Tissue levels of NO3-/NO2- increased significantly in the kidneys, small intestines, heart, and liver at 10 h but not at 5 h after CLP. Similarly, iNOS gene expression was upregulated in the kidneys, small intestines, and liver. Thus, the above organs appear to be important sites responsible for producing the increased NO during sepsis. Because we previously showed that the hyperdynamic response occurs as early as 2 h after CLP and because iNOS-derived NO production is not upregulated earlier than 10 h after the onset of Sepsis, it appears that factors other than NO are responsible for producing the hyperdynamic response during sepsis.

Animals↗

PubMed2000

Effect of gender and sex hormones on immune responses following shock.

Several clinical and experimental studies show a gender dimorphism of the immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses are depressed in males after trauma-hemorrhage, whereas they are unchanged or enhanced in females. Sex hormones contribute to this gender-specific immune response after adverse circulatory conditions. Specifically, studies indicate that androgens are responsible for the immunodepression after trauma-hemorrhage in males. In contrast, female sex steroids seem to exhibit immunoprotective properties after trauma and severe blood loss, because administration of estrogen prevents the androgen-induced immunodepression in castrated male mice. Nonetheless, the precise underlying mechanisms for these immunomodulatory effects of sex steroids after shock remain unknown. Although testosterone depletion, testosterone receptor antagonism, or estrogen treatment has been shown to prevent the depression of immune functions after trauma-hemorrhage, it remains to be established whether differences in the testosterone-estradiol ratio are responsible for the immune dysfunction. Furthermore, sex hormone receptors have been identified on various immune cells, suggesting direct effects. Thus, the immunomodulatory properties of sex hormones after trauma-hemorrhage might represent novel therapeutic strategies for the treatment of immunodepression in trauma patients.

Androgen Antagonists↗

PubMed2000

The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis.

Studies have shown that immune responses are depressed in male mice, but not in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice. These gender-specific alterations in immune function are believed to be due to differences in sex steroid levels. Aromatase is a key enzyme in the sex steroid biosynthesis. Although earlier studies have shown that aromatase inhibitors prevent thymic atrophy in aged male rats, it remains unknown whether the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has any salutary effects on the depressed immune responses. Male C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30+/-5 mmHg for 90 min) followed by adequate fluid resuscitation. 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resuscitation. At 2 h after resuscitation, the mice were killed, and spleens were harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN-gamma), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) were assessed. In another group, sepsis was induced by cecal ligation and puncture (CLP) 3 days after resuscitation, and survival was measured over a period of 10 days. A significant decrease in splenocyte proliferation, IL-2, and IFN-gamma release and increased release of IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA showed increased splenocyte proliferation, IL-2, and IFN-gamma release, and decreased IL-10 release. Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclear ER-alpha and -beta expression was observed in the vehicle-treated group after TH. In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH. ER-alpha expression decreased and ER-beta expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot. There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER-beta mRNA expression was unaffected, whereas ER-alpha expression increased under such conditions. In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment. Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depressed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis.

Androstenedione↗