Biomedical subjects

I H Chaudry

Publications and source records attributed to I H Chaudry.

At least 163 records · Page 9Linked to original sources

PubMed1996

Increased melatonin levels after hemorrhagic shock in male and female C3H/HeN mice.

Although hemorrhagic shock leads to significant alterations of several hormones, e.g. ACTH, corticosterone and beta-endorphin, it is not known whether plasma melatonin levels are affected under this condition and if so, whether the effects are comparable in males and females. Using a radioimmunoassay, it was found that plasma melatonin levels were significantly increased in male and proestrus female C3H/HeN mice immediately after hemorrhagic shock. However, in male mice, by two hours after hemorrhage and resuscitation, plasma melatonin returned to levels comparable to those seen in control and sham-operated animals. Proestrus female mice, on the other hand, showed significantly increased plasma melatonin levels at two hours after surgery when compared to unoperated control animals. Although the significance and biological role of the transient increased plasma melatonin levels after hemorrhagic shock remain to be determined, it appears that the pineal gland and/or an extrapineal source of melatonin, of both male and proestrus female mice responds to severe hypotension by increased release of melatonin.

Animals↗

PubMed1996

Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators.

Apoptosis (Ao), is a process by which cells undergo a form of nonnecrotic cellular suicide. Although for most cells this is a constitutive process, it can be induced in immature and differentiating immune cell populations by stress mediators associated with inflammation. This inducible form of A(o) is referred to as programmed cell death. However, it is not clear whether hematopoietic cell populations such as the thymus and bone marrow are induced to undergo A(o) during polymicrobial sepsis. To assess this, thymocytes, bone marrow cells, or splenocytes (as a source of comparative nonhematopoietic cells) were harvested from C3H/HeN mice at 1, 4, or 24 hours after cecal ligation and puncture (CLP; to induce polymicrobial sepsis) or sham-CLP (Sham). The results showed that mixed bone marrow cells ex vivo, although not to the same extent as thymus, showed a marked increase in the percentage of cells in A(o), increased endonuclease activity, and a significant decrease in cell yield at 24 hours but not at 4 hours after CLP. Similar changes were not evident in splenocytes. Phenotypic, as well as morphologic assessment, indicated that most of the increase in apoptotic cells in the thymus was associated with the immature T cells (CD4+CD8+) and CD8-CD4- cells. In contrast, the increase in bone marrow cell A(o) was associated with only the B220+ cells, with no significant contribution from myeloid cells. Treatment of CLP mice in vivo with either RU-38486 or PEG-(rsTNF-R1)2 was unable to reverse the increased A(o) in the bone marrow of these animals. Taken together, these findings indicate that A(o) as a process induced by polymicrobial sepsis is not limited to the thymus, but can also be detected in the bone marrow. However, unlike thymic A(o), bone marrow is not affected directly/indirectly by glucocorticoids or tumor necrosis factor released during sepsis.

Animals↗

PubMed1996

Immune function is more compromised after closed bone fracture and hemorrhagic shock than hemorrhage alone.

OBJECTIVE: To determine whether closed bone fracture in conjunction with hemorrhagic shock compromises immune functions more severely than hemorrhagic shock alone. DESIGN: In a randomized, controlled trial, closed bone fracture of the right lower leg and/or hemorrhagic shock (mean +/- SEM arterial blood pressure, 35 +/- 5 mm Hg for 90 minutes) were induced in male C3H/HeN mice (weight, 25 g). Animals subjected to hemorrhage were resuscitated with the shed blood and lactated Ringer solution. At 72 hours after the experiment, all animals were killed to obtain whole blood, splenocytes, and splenic and peritoneal macrophages. Macrophage interleukin-1 and splenocyte interleukin-2 and interleukin-3 release were determined by bioassay, and splenocyte proliferation was measured by tritiated thymidine incorporation. RESULTS: Closed bone fracture alone did not affect immune functions 72 hours after the trauma. Hemorrhagic shock, however, induced a significant depression of splenocyte and macrophage functions. Bone fracture followed by hemorrhagic shock further depressed splenocyte proliferation and splenocyte interleukin-2 and interleukin-3 release as well as interleukin-1 release. CONCLUSION: Since bone injury coupled with hemorrhagic shock produces more severe depression of immune functions than hemorrhage alone, bone injury appears to play a contributory role in further depressing immune functions in trauma patients who experience major blood loss.

Animals↗

PubMed1996

Mechanism of immunosuppression in males following trauma-hemorrhage. Critical role of testosterone.

OBJECTIVE: To determine whether male sex steroids contribute to the depression in cell-mediated immunity following trauma-hemorrhage and resuscitation. DESIGN: Two weeks before the induction of soft-tissue trauma (2.5-cm midline laparotomy) and hemorrhagic shock (mean [+/-SEM] blood pressure, 35 +/- 5 mm Hg), male C3H/HeN mice were castrated or sham castrated. Following trauma-hemorrhage, the mice were resuscitated and killed 24 hours thereafter to obtain whole blood and the spleen. RESULTS: Splenocyte proliferation and splenocyte interleukin-2 and interleukin-3 release were significantly depressed in sham-castrated animals after trauma-hemorrhage. In contrast, these variables in castrated mice after trauma-hemorrhage were similar to those in sham-operated animals. Corticosterone plasma levels were significantly elevated in both trauma-hemorrhage groups compared with those in sham-operated mice. Plasma testosterone levels were undetectable in castrated animals and detectable in sham-castrated mice. CONCLUSIONS: Castration before soft-tissue trauma and hemorrhagic shock maintains normal immune function in male mice, but sham-castrated male mice show significant immunodepression. The maintenance of immune function by androgen deficiency does not seem to be related to changes in the release of corticosterone. We conclude that male sex steroids are involved in the immunodepression observed after trauma-hemorrhage. Thus, the use of testosterone-blocking agents following trauma-hemorrhage should prevent the depression of immune functions and decrease the susceptibility to sepsis under those conditions.

Androgens↗

PubMed1996

Depressed splenic function after hemorrhage results from gastrointestinal tract stimulation of hepatic-mediator release. Correction with portacaval shunt.

OBJECTIVE: To determine whether redirecting intestinal blood flow away from the liver via a portacaval shunt would protect distal immune responses in the spleen after hemorrhage. DESIGN: Type C3H/HeN male mice in which a portacaval shunt had been established 2 to 3 weeks before the experiment were bled, their blood pressure was maintained at 35 mm Hg for 1 hour, and then they were resuscitated. Twenty-four hours later, the mice were killed, and mixed and adherent splenocyte cultures were established. The proliferative capacity of splenocytes, the release of interleukin-2 and interleukin-4, and the ability of splenic macrophages to present the antigen, conalbumin, were then determined as indexes of immunocompetence. RESULTS AND CONCLUSIONS: The results indicate that splenocyte proliferation and splenocyte interleukin-2, but not interleukin-4, release were decreased and that splenic macrophage antigen presentation declined after hemorrhage. However, animals in which a portacaval shunt had been established before hemorrhage showed no such changes in their splenocyte or splenic macrophage functions. Thus, the decline of splenic immune responses after hemorrhage seems to be due to mediators released from the gut. Such mediators, in turn, stimulate Kupffer cells to secrete additional agents that produce immunosuppressive exocrine effects on splenic immune functions.

Animals↗

PubMed1996

Prolactin inhibits the increased cytokine gene expression in Kupffer cells following haemorrhage.

Kupffer cells are an important source of proinflammatory cytokines and contribute to the systemic inflammatory response observed following haemorrhagic shock. The systemic release of cytokines, such as TNF-alpha, IL-1 beta, IL-6, etc., has been associated with the decreased host immune and organ dysfunction following hypotension. Studies indicate that anterior pituitary hormone prolactin (PRL) plays an important role in the regulation of lymphocyte proliferation and macrophage function in vivo, as well as in vitro. However, it is not known what effects PRL administration has on Kupffer cells proinflammatory mediator release following haemorrhage. Therefore, it was the aim of this study to determine the effect of in vivo PRL administration on cytokine gene expression in Kupffer cells after haemorrhage. To study this, C3H/HeN male mice were bled to and maintained at a mean arterial pressure of 35 mmHg for 60 minutes, then resuscitated with shed blood, and segregated into two groups: one group was treated with PRL (100 micrograms/25 g body weight subcutaneously) while the other group received saline-vehicles. This was followed with lactated Ringer's solution (2 x the volume of shed blood). Two hours thereafter, the animals were sacrificed, Kupffer cells were isolated and stimulated with or without 10 micrograms/ml LPS for 1 hour. Total RNA was extracted and cytokine mRNA was detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results demonstrated that haemorrhage markedly increased the level of mRNA for IL-1 beta, IL-6, TGF-beta and TNF-beta in Kupffer cells. However, in vivo PRL treatment significantly decreased the cytokine gene expression in Kupffer cells following haemorrhage. This indicates that PRL may be useful in blunting the systemic inflammatory response associated with cell and organ depression following shock.

Animals↗

PubMed1996

Enhanced immune responses in females, as opposed to decreased responses in males following haemorrhagic shock and resuscitation.

Although haemorrhagic shock produces immunodepression in both humans and experimental animals, no information is available concerning gender differences in the immune and endocrine response to shock. To study this, male and female (proestrus and diestrus) C3H/HeN mice (25 g body weight) were bled and maintained at a mean arterial blood pressure of 35 +/- 5 mmHg for 1 h and then adequately resuscitated. The animals were killed at 2 h after resuscitation to obtain splenocytes, macrophages (M phi, peritoneal and splenic), as well as whole blood. IL-1 release by M phi, splenocyte proliferative capacity and splenocyte IL-3 release in female mice was significantly increased. Male mice, however, showed decreased release of all interleukins (IL-1, 2, 3, 6) as well as splenocyte proliferative capacity after shock. Plasma corticosterone levels decreased in proestrus female mice, as opposed to increased levels in males following shock. Corticosterone may therefore, be in part responsible for the observed gender differences. To the authors' knowledge, this is the first study which shows that immune responsiveness in female mice is enhanced after haemorrhagic shock, as opposed to decreased responsiveness in males. Thus, unlike males which exhibit increased susceptibility to sepsis/infections, females should be able to better tolerate the deleterious effects of shock.

Animals↗

PubMed1996

Relationship of pelvic radiation to intestinal blood flow.

Pelvic radiation remains the mainstay in the treatment of many malignancies. Chronic radiation injury represents an obliterative endarteritis. The purpose of our experiment was to investigate the chronic changes in blood flow that occurred in a model of pelvic radiation. Also, we investigated the potential benefits of an elemental diet, sodium meclofenamate, and vitamin A within the radiated large and small bowel. Female Sprague-Dawley rats, 200-250 g, were anesthetized and received 900 rads once a week for 5 weeks for a total of 4500 rads. Group B received sodium meclofenamate, group C elemental diet, and group D vitamin A. Group A received radiation only where control animals (group E) received anesthesia but no radiation. All animals were given treatments during the course of radiation therapy only. Blood flow was determined within the terminal ileum, proximal jejunum, and distal colon 1 week, 5 weeks, 6 months, and 1 year postradiation therapy. Blood flow was determined by strontium-labeled 15-microns microspheres. Results showed that radiation resulted in an increase in blood flow within the terminal ileum at 1 week postradiation of approximately 175% when compared to controls. Blood flow then decreased (59%) when compared to controls at 5 weeks and increased (141%) again at 6 months when compared to controls. No change in blood flow was noted at 1 year postradiation therapy. An elemental diet and sodium meclofenamate prevented these changes in blood flow at each of these times points. No change in blood flow was seen at any of the time points measured within the jejunum or colon.

Animals↗

PubMed1996

Prolactin: a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage.

Recent studies have shown that the anterior pituitary hormone prolactin, together with various cytokines, plays an important role in maintaining normal immune responses. Although there is evidence that prolactin may be a significant immunotropic hormone that can counteract the immunosuppressive effects of drugs such as cyclosporine, morphine, or glucocorticoids, it remains unknown whether prolactin administration has any salutary effects on the depressed immune responses following severe hemorrhage. To study this, mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 min, then adequately resuscitated and segregated into two groups. One group received saline-vehicle (hem-SS); animals in the other group were treated with prolactin (hem-PRL) (100 micrograms per 25 g BW, subcutaneously) immediately before resuscitation. Two hours following saline or prolactin injection, splenocytes (SPL) were harvested and assessed for proliferative capacity (PC) and their ability to release IL-2 and IL-3. Supernatant lymphokine levels were determined by bioassay. The proliferative capacity of the splenocytes, as well as their ability to release IL-2 and IL-3, was significantly depressed in the vehicle-treated hemorrhaged animals, compared to shams. Treatment with prolactin restored the depressed splenocyte functions seen after severe hemorrhage. These results support the notion that the immunosuppression following hemorrhage and trauma may be mediated by hormones from the hypothalamic-pituitary-adrenal axis. Furthermore, our results suggest that the use of prolactin, which did not produce any adverse hemodynamic effects, represents a novel and safe immunomodulating hormone for the treatment of immunodepression following severe blood loss.

Animals↗

PubMed1996

Melatonin administration attenuates depressed immune functions trauma-hemorrhage.

The pineal hormone melatonin has been used in clinical trials in patients suffering from AIDS and also as an adjuvant for cancer therapy. Although melatonin has been reported to have beneficial effects in some animal models of immune dysfunction, it remains unknown whether this hormone has any salutary effects on immunity following soft-tissue trauma and/or major blood loss. To study this, soft-tissue trauma (2.5-cm midline laparotomy) and hemorrhagic shock (arterial BP 35 +/- 5 mm Hg) were induced in C3H/HeN mice. The mice were resuscitated after 90 min of hypotension with the shed blood and lactated Ringer's solution. Treatment with saline, vehicle, or melatonin (10 mg/kg BW) subcutaneously was administered in the evening of the day of surgery and again on the following evening. All animals were sacrificed at 48 hr following trauma-hemorrhage and resuscitation to obtain plasma, splenocytes, as well as splenic and peritoneal macrophages (Mphi). The results indicate that melatonin administration after trauma-hemorrhage significantly improved the depressed immune functions, as evidenced by the restoration of Mphi IL-1 and IL-6 release, as well as significantly improved splenocyte IL-2 and IL-3 release and splenocyte proliferative capacity. No differences in circulating corticosterone levels between vehicle- and melatonin-treated animals were observed. This is the first study to show that melatonin, which is reported to be free of adverse side effects, can be considered a safe and effective therapeutic agent for restoring the depressed immunological function after soft-tissue trauma and hemorrhagic shock.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge.

Melatonin administration has been reported to have beneficial effects on immune function in some clinical studies and in several animal models of immune dysfunction. Furthermore, recent studies suggest beneficial effects of melatonin on depressed immune function following trauma-hemorrhage. Nonetheless, it remains unknown whether this hormone has any salutary effects on survival following hemorrhagic shock and subsequent septic challenge. Male C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 +/- 5 mm Hg for 90 min, adequately resuscitated, and 48 hr thereafter subjected to sepsis (cecal ligation and puncture; CLP). Melatonin-treated mice received either short-term treatment on Days 1 and 2 after hemorrhage or continuous treatment throughout the study. Treatment with vehicle (10% ethanol in normal saline) or melatonin (10 mg/kg body weight) was administered daily starting in the evening of the day of hemorrhage/sham-operation. Short-term melatonin administration after hemorrhage significantly improved survival in animals subjected to septic challenge. Continuous melatonin treatment did not improve survival, as compared to vehicle-treated mice subjected to shock and CLP. Moreover, continuous melatonin treatment in sham-operated animals significantly increased mortality compared to short-term-treated and vehicle-treated animals. While the mechanisms of the differential effects of melatonin administration are yet to be clearly defined, this study, nonetheless, demonstrates the salutary effects of short-term melatonin administration in the treatment of immune dysfunction following hemorrhagic shock.

Animals↗

PubMed1996

Pentoxifylline restores the depressed cardiac performance after trauma-hemorrhage and resuscitation.

Although studies have shown that pentoxifylline (PTX) improves tissue perfusion and hepatocellular function after trauma-hemorrhage and resuscitation, it is not known whether this agent has any beneficial effects on left ventricular performance under such conditions. To study this, rats underwent laparotomy (i.e., trauma induced) and were bled to and maintained at a blood pressure of 40 mm Hg until 40% of the maximum shed blood volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of shed blood with Ringer's lactate over 60 min, following which PTX (50 mg/kg body wt) or an equivalent volume of normal saline was infused intravenously over 100 min. Maximum dP/dt during contraction (+dP/dtmax) and relaxation (-dP/dtmax), maximum rate of a "pressure-normalized" change in ventricular pressure during ventricular contraction (dP/dtmax/P), and ventricular peak systemic pressure (VPSP) were determined at 15 min before the completion of resuscitation and every 30 min up to 4 hr after resuscitation. The results indicated that both +dP/dtmax and -dP/dtmax decreased significantly beginning at 0.5 h after resuscitation and remained depressed throughout the study period in saline-treated animals. In addition, VPSP was significantly depressed at 2.5 to 4 hr after resuscitation. Treatment with PTX, however, significantly improved the above parameters as well as dP/dtmax/P and heart rate. Since PTX restores various left ventricular performance parameters, this agent appears to be a useful adjunct for improving cardiac function after trauma and hemorrhagic shock, even in the absence of blood resuscitation.

Animals↗

PubMed1996

Pentoxifylline maintains vascular endothelial cell function during hyperdynamic and hypodynamic sepsis.

BACKGROUND: Although pentoxifylline produces various beneficial effects after endotoxemia or sepsis occurs, it is not known whether this agent attenuates the depressed endothelial cell function during sepsis. Therefore the aim of this study was to determine whether pentoxifylline maintains vascular endothelial cell function (i.e., improves the release of endothelium-derived nitric oxide) during hyperdynamic and hypodynamic stages of polymicrobial sepsis. METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP), after which 3 ml/100 gm body wt normal saline solution was injected subcutaneously in these and rats in a sham-operated group. At 1 hour after the onset of sepsis, pentoxifylline (50 mg/kg body wt) or an equal volume of normal saline solution was infused intravenously during a 30 minute period. At 10 and 20 hours after CLP was performed (10-hour CLP, hyperdynamic sepsis; 20-hour CLP, hypodynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) mol/L) was used to achieve near maximal tension. Dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were carried out. The changes in percentage relaxation in the aortic rings by these agonists were then determined. RESULTS: Endothelium-dependent (acetylcholine-induced) vascular relaxation decreased significantly at 10 and 20 hours after CLP. Administration of pentoxifylline, however, maintained acetylcholine-induced vascular relaxation at both time points. In contrast, no significant reduction in nitroglycerine-induced vascular relaxation was seen in rats with sepsis irrespective of pentoxifylline treatment. CONCLUSIONS: Because pentoxifylline prevented endothelial cell dysfunction at 10 and 20 hours after CLP occurred, this agent appears to be a useful agent for maintaining vascular endothelial function during the hyperdynamic and hypodynamic stages of polymicrobial sepsis.

Acetylcholine↗

PubMed1996

Is sepsis-induced apoptosis associated with macrophage dysfunction?

Apoptosis (A O) is a pathological process by which cells undergo a form of inducible nonnecrotic cellular suicide. In vitro studies suggest that changes in the rate of macrophage (Mo) A O may be associated with elevated proinflammatory cytokine secretory capacity, such as interleukin-1 beta (IL-1 beta) (via IL-1 converting enzyme activation). Furthermore, it has been reported that Mo are activated during early (0-4 hours) experimental septic insult to act as sources of proinflammatory cytokines, such as IL-1. However, with the progression of sepsis, these same cells become refractory to further stimulation (appearing dysfunctional). Nonetheless, it remains unknown if this acquired immunosuppression (dysfunction) is associated with an acceleration in macrophage A O. To determine this, male C3H/HeN mice were subjected to sepsis (cecal ligation and puncture, CLP) or sham-CLP and 4 or 24 hours thereafter Mo were isolated from the peritoneum (PMo) and liver (KMo). Macrophage monolayers were lysed either after stimulation with lipopolysaccharide (LPS) (10 microgram/mL, 24 hours) in vitro or immediately (ex vivo) before LPS stimulation and the cytoplasmic cell fraction was retained. The extent of A O was determined using a cell-death enzyme-linked immunosorbent assay, which detects the presence of cytoplasmic oligonucleosomes and changes in the propidium iodide staining intensity. The results indicate that, early after CLP (4 hours) only PMo stimulated with LPS in vitro showed evidence of increasing A O. At 24 hours (late) after the onset of sepsis, the ex vivo extent of A O in PMo was increased but it was decreased in KMo. However, the addition of LPS in vitro results in a marked increase in both septic PMo and KMo A O. This latter result suggests that the inability of Mo to release cytokines in response to stiumulants, such as LPS during late sesis (24 hours), may be because of induciton of accelerated A O in these Mo populations.

Animals↗

PubMed1996

Inhibition of the biologic activity of tumor necrosis factor maintains vascular endothelial cell function during hyperdynamic sepsis.

BACKGROUND AND OBJECTIVE: Although vascular endothelial cell function (i.e., the release of endothelium-derived nitric oxide) decreases and plasma tumor necrosis factor (TNF) increases during sepsis, it is not known whether the elevated TNF is responsible for the depression of endothelial cell function under such conditions. The aim of this study, therefore, was to determine if inhibition of TNF biologic activity by polyethylene glycol dimerized conjugate of the recombinant human form of the p55 soluble TNF receptor (PEG-(rsTNF-R1)2) maintains endothelial function during sepsis. DESIGN, MATERIALS AND METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP). Immediately before the onset of sepsis, 600 microgram/rat PEG-(rsTNF-R1)2 or an equal volume of saline was infused intravenously. At 10 hours after CLP (i.e., hyperdynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers. Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerine (NTG), were determined. Endothelial cell structure was examined by transmission electron microscopy. RESULTS: Endothelium-dependent vascular relaxation was depressed at 10 hours after the onset of sepsis. Administration of PEG-(rsTNF-R1)2 before CLP, however, maintained ACh-induced relaxation. In contrast, no significant difference in NTG-induced relaxation was seen, irrespective of administration of PEG-(rsTNF-R1)2 Furthermore, the deterioration in endothelial structure during sepsis was prevented by PEG-(rsTNF-R1)2 pretreatment. CONCLUSION: Since administration of PEG-(rsTNF-R1)2 maintains vascular endothelial cell structure and function, it can be concluded that TNF plays a pivotal role in producing endothelial dysfunction during sepsis. Thus, pharmacologic agents that inhibit TNF biologic activity and/or its production may be useful for protecting endothelial cells during sepsis.

Acetylcholine↗

PubMed1996

Depressed osteoblast activity and increased osteocyte necrosis after closed bone fracture and hemorrhagic shock.

BACKGROUND: Although bone fracture and hemorrhagic shock are frequent complications in trauma patients, it remains unknown whether hemorrhagic shock after bone fracture produces any deleterious effects on osteoblast function and osteocyte necrosis. METHODS: Sham-operation, closed bone fracture (right tibia) with and without hemorrhagic shock (mean arterial blood pressure 35 +/- 5 mm Hg for 90 minutes followed by fluid resuscitation) were induced in 18 male C3H/HeN mice (25 g body weight) At 72 hours after the experiment, all animals were killed, whole blood was obtained by cardiac puncture, and plasma assayed for circulating levels of osteocalcin. RESULTS: Plasma osteocalcin levels were found to be significantly depressed after closed bone fracture in conjunction with hemorrhagic shock. Closed bone fracture alone increased plasma osteocalcin. Histologic analysis of the fracture sites revealed that hemorrhagic shock after closed bone fracture significantly increased osteocyte necrosis adjacent to the fracture site, when compared to animals with closed bone fracture alone. CONCLUSIONS: These findings suggest that severe hemorrhage after closed bone fracture depresses osteoblast activity and increases osteocyte necrosis, which should compromise fracture healing under those conditions.

Animals↗

PubMed1996

Trauma-induced suppression of antigen presentation and expression of major histocompatibility class II antigen complex in leukocytes.

The immune response to trauma, shock, and/or sepsis appears to exhibit a bimodal response, in which there is an early exaggerated inflammatory response, giving way over time to a state of hyporesponsiveness or immune dysfunction. This state of immune dysfunction is frequently associated with increased infectious complications and/or mortality, seen following shock or trauma. In this article, we present an overview of some of those changes that have been seen with respect to the process of major histocompatibility class II (MHC class II) antigen presentation by macrophage, a key component of the overall host immune response to foreign bacterial and/or fungal pathogens encountered following shock/trauma (with a particular emphasis on hemorrhagic shock as a component of traumatic shock). With respect to the overall process of antigen presentation, defects (dysfunction) are evident not only in models of shock and sepsis, but also in traumatized patients. Studies of the capacity of a monocyte's/macrophage's ability to present antigen indicate that defects can be detected, not only in those steps involved in antigenic processing, but also in MHC class II molecule expression and accessory molecule function (or its inhibition) following shock. Those changes in the macrophage's capacity to process antigen seen during the first 24 h after hemorrhagic shock appear to be associated with the cell's metabolic response to regional hypoxia and/or the shift to proinflammatory mediator release (tumor necrosis factor, interleukin [IL]-1, IL-6, etc.). This initial acute response to shock appears to act as the nidus for chronic anti-inflammatory mediator release (prostaglandin E2, transforming growth factor-beta, IL-10, IL-4, nitric oxide, etc.), which may mediate the sustained depression of the antigen-presenting cell's function.

Animals↗

PubMed1996

A novel nonanticoagulant heparin prevents vascular endothelial cell dysfunction during hyperdynamic sepsis.

Although a novel nonanticoagulant heparin (i.e., GM1892) produces various beneficial effects after hemorrhage and resuscitation, it remains unknown whether this agent has any salutary effects on the depressed vascular endothelial cell function during sepsis. To determine this, rats were subjected to sepsis by cecal ligation and puncture (CLP). At 1 h after CLP, GM1892 (7 or 14 mg/kg body wt), conventional heparin (7 or 14 mg/kg), or an equal volume of saline was administered intravenously. At 5 h after CLP (i.e., hyperdynamic sepsis), the thoracic aortae were isolated and placed in organ chambers. Dose-response relaxation curves were determined for acetylcholine (ACh; 10(-8) to 10(-5) M), which stimulates endothelial nitric oxide production, and for nitroglycerine (10(-9) to 10(-6) M), which directly provides nitric oxide in vivo. ACh-induced relaxation was depressed at 5 h after CLP while there was no significant alteration in nitroglycerine-induced relaxation. Treatment with 14 mg/kg GM1892 or 14 mg/kg heparin (but not with 7 mg/kg GM1892 or 7 mg/kg heparin), however, prevented the decrease of ACh-induced relaxation. Thus, GM1892 (which does not possess any significant anticoagulant properties) at the higher dosage appears to be useful for maintaining vascular endothelial cell function during hyperdynamic sepsis.

Acetylcholine↗