Biomedical subjects

T R Billiar

Publications and source records attributed to T R Billiar.

At least 91 records · Page 5Linked to original sources

PubMed1999

Novel roles of nitric oxide in hemorrhagic shock.

The aim of the current article is to overview the recent developments in the field of hemorrhagic shock research, as it relates to the roles of nitric oxide (NO) in the pathogenesis of this condition. The first part of the review focuses on the roles of peroxynitrite, a reactive oxidant produced from the reaction of NO and superoxide. The second part of the review deals with the novel findings related to the recently identified regulatory roles of the inducible isoform of nitric oxide synthase (iNOS) in the expression of pro-inflammatory mediators in hemorrhagic shock. (1) The role of peroxynitrite: Immunohistochemical and biochemical evidence demonstrate the production of peroxynitrite in hemorrhagic shock. Peroxynitrite can initiate a wide range of toxic oxidative reactions. These include initiation of tyrosine nitration, lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of hemorrhagic shock. A combined anti-inflammatory agent, mercaptoethylguanidine, which selectively inhibits iNOS and scavenges peroxynitrite, prevents the delayed vascular decompensation and the cellular energetic failure associated with late hemorrhagic shock. Peroxynitrite is a potent trigger of DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Pharmacological inhibition of PARS, with 3-aminobenzamide or 5-iodo-6-amino-1,2-benzopyrone, improves hemodynamic status and prolongs survival time in rodent and porcine models of severe hemorrhagic shock. (2) Novel signaling roles of induced NO in hemorrhagic shock. Although the severity and duration of shock may dictate the timing and extent of iNOS expression, it is now evident that the up-regulation of iNOS can take place during sustained shock. Accumulated data indicate that iNOS expressed during shock contributes to vascular decompensation, as classically described by Wiggers. In addition, the presence of even low levels of iNOS at the time of resuscitation enhances the inflammatory response that follows the reperfusion state. Pharmacological inhibition of iNOS with N6-(iminoethyl)-L-lysine or genetic inactivation of iNOS (iNOS knockout mice) attenuates the activation of the transcription factors nuclear factor kappa B (NFkappaB) and Signal Transducer and Activator of Transcription 3 (STAT3), and ameliorates the increases in interleukin-6 and G-CSF messenger RNA levels in the lungs and liver. Inhibition of iNOS results in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide, in addition to being a "final common mediator" of hemorrhagic shock, is essential for the up-regulation of the inflammatory response in resuscitated hemorrhagic shock. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of peroxynitrite, with its associated toxicities, and indirectly through the amplification of the inflammatory response.

Animals↗

PubMed1999

Nitric Oxide. IV. Determinants of nitric oxide protection and toxicity in liver.

Whereas nitric oxide (NO) produced by constitutive endothelial NO synthase is protective to the liver, NO produced by the inducible NO synthase (iNOS) can be either toxic or protective depending on the conditions. The availability of selective iNOS inhibitors and mice lacking various NOS isoforms made it possible to begin to elucidate the precise roles of NO in the liver. Under conditions of redox stress, induced NO contributes to hepatic damage. However, in acute inflammatory conditions associated with cytokine exposure, NO acts as a potent inhibitor of apoptosis in the liver. Our current understanding of the mechanisms by which NO exerts both hepatoprotective and hepatotoxic actions is discussed in this themes article.

Animals↗

PubMed1999

A novel nitric oxide scavenger decreases liver injury and improves survival after hemorrhagic shock.

We tested the ability of a nitric oxide (NO) scavenger to reduce tissue injury in a rodent model of hemorrhagic shock. Rats were hemorrhaged to a mean arterial blood pressure (MAP) of 40 mmHg and then resuscitated when either 30% of their shed blood had been returned (group 1) or after 100 min of continuous shock (group 2). Selected animals were treated with the NO scavenger NOX (30 mg. kg(-1). h(-1)) infused over 4 h. Hemorrhaged rats had a lower MAP after resuscitation compared with sham-shock control rats. NOX treatment significantly increased MAP after resuscitation from hemorrhage. Hemorrhagic shock also increased liver injury as reflected by elevated ornithine carbamoyltransferase (OCT) plasma levels, and NOX treatment significantly reduced OCT release. In addition, NOX was associated with significantly decreased hepatic neutrophil infiltration and improved 24-h survival (n = 8 of 9) compared with saline-treated shock animals (n = 3 of 9). These data suggest that excess NO mediates shock-induced tissue injury and that suppression of NO availability with NO scavengers may reduce the pathophysiological sequelae of severe hemorrhage.

Animals↗

PubMed1999

LPS-induced muscularis macrophage nitric oxide suppresses rat jejunal circular muscle activity.

Cellular mechanisms of sepsis-induced ileus remain an enigma. The study aim was to determine the role of nitric oxide (NO) in mediating the suppression of rat jejunal circular smooth muscle activity during endotoxemia. Isolated muscularis inducible NO synthase (iNOS) mRNA was measured by RT-PCR, immunohistochemistry was employed to localize iNOS protein, and contractile activity was measured in an organ bath. The low basal expression of muscularis iNOS mRNA expression was increased in a time-dependent fashion after lipopolysaccharide (LPS), resulting in a 20-fold increase over controls 3 h after injection. Immunohistochemistry of muscularis whole mounts and dissociated muscularis cells for iNOS revealed staining only in the muscularis macrophages 12 h after LPS. LPS caused a 68% reduction in spontaneous muscle activity 12 h after injection, which improved by 53% after the in vitro application of the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine. Similar results were obtained in C57BL/6 mice but not in iNOS knockout mice. These data demonstrate that macrophage iNOS plays an important role in mediating LPS-induced intestinal circular muscle suppression.

Animals↗

PubMed1999

Impaired wound healing and angiogenesis in eNOS-deficient mice.

A role for nitric oxide (NO) in wound healing has been proposed; however, the absolute requirement of NO for wound healing in vivo and the contribution of endothelial NO synthase (eNOS) have not been determined. Experiments were carried out using eNOS gene knockout (KO) mice to determine the requirement for eNOS on wound closure and wound strength. Excisional wound closure was significantly delayed in the eNOS KO mice (29.4 +/- 2.2 days) compared with wild-type (WT) controls (20.2 +/- 0.4 days). At 10 days, incisional wound tensile strength demonstrated a 38% reduction in the eNOS KO mice. Because effective wound repair requires growth factor-stimulated angiogenesis, in vitro and in vivo angiogenesis assays were performed in the mice to assess the effects of eNOS deficiency on angiogenesis. Endothelial cell sprouting assays confirmed in vitro that eNOS is required for proper endothelial cell migration, proliferation, and differentiation. Aortic segments harvested from eNOS KO mice cultured with Matrigel demonstrated a significant reduction in endothelial cell sprouting and [(3)H]thymidine incorporation compared with WT mice at 5 days. Capillary ingrowth into subcutaneously implanted Matrigel plugs was significantly reduced in eNOS KO mice (2.67 +/- 0.33 vessels/plug) compared with WT mice (10.17 +/- 0.79 vessels/plug). These results clearly show that eNOS plays a significant role in facilitating wound repair and growth factor-stimulated angiogenesis.

Animals↗

PubMed1999

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice.

Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1. 5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS(-/-)) were compared with wild-type (iNOS(+/+)) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS(+/+) and iNOS(-/-) mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS(-/-) mice showed markedly worse performance in the MWM task than iNOS(+/+) mice. A beneficial role for iNOS in TBI is supported.

Animals↗

PubMed1999

Optimization of ex vivo inducible nitric oxide synthase gene transfer to vein grafts.

BACKGROUND: Vein graft failure as the result of intimal hyperplasia (IH) remains a significant clinical problem. Ex vivo modification of vein grafts using gene therapy is an attractive approach to attenuate IH. Gene transfer of the inducible nitric oxide synthase (iNOS) gene effectively reduces IH. However, iNOS activity after gene transfer may be impaired by the availability of cofactor, such as tetrahydrobiopterin (BH4). The purpose of this study is to determine the optimal conditions for ex vivo adenoviral-mediated iNOS gene transfer into arterial and venous vessels. METHODS: Porcine internal jugular veins and carotid arteries were infected ex vivo with the adenoviral iNOS vector (AdiNOS) and with an adenovirus carrying the cDNA encoding guanosine triphosphate cyclohydrolase I (AdGTPCH), the rate-limiting enzyme for BH4 synthesis. The production of nitrite, cyclic guanosine monophosphate (cGMP), and biopterin were assessed daily. RESULTS: Nitric oxide (NO) production after iNOS gene transfer was maximal when vessels were cotransduced with AdGTPCH. NO production in these vessels persisted for more than 10 days. Vein segments generated approximately 2-fold more nitrite, cGMP, and biopterin than arterial segments infected with AdiNOS/AdGTPCH. Submerging vein segments into adenoviral solution resulted in improved gene transfer with greater nitrite and cGMP release compared with infections carried out under pressure intraluminally. Similarly, injury to the vein segments before infection with AdiNOS resulted in less nitrite production. CONCLUSIONS: These data demonstrate that AdiNOS can efficiently transduce vein segments ex vivo and that the cotransfer of GTPCH can optimize iNOS enzymatic activity. This cotransfer technique may be used to engineer vein grafts before coronary artery bypass to prevent IH.

Adenoviridae↗

PubMed1999

Gene therapy and tissue engineering.

Gene therapy, the science of altering cellular function or structure at a molecular level, is currently one of the most exciting fields of research across medical specialties. By replacing lost or defective genes or adding genes known to produce proteins with beneficial effects, investigators hope to treat and possibly cure everything from inborn errors of metabolism to acquired diseases, such as emphysema and atherosclerosis. Genetic modification of engineered tissue, the offspring of these two fields, offers the promise of not simply replacing tissue, but improving on the restoration. The studies presented in this article demonstrate many of the principles that form the basis of gene therapy and provide insight into the potential of this emerging technology.

Animals↗

PubMed1998

Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bcl-2 cleavage and cytochrome c release.

It is now known that caspase-3-like protease activation can promote Bcl-2 cleavage and mitochondrial cytochrome c release and that these events can lead to further downstream caspase activation. NO has been proposed as a potent, endogenous inhibitor of caspase-3-like protease activity. Experiments were carried out to determine whether NO could interrupt Bcl-2 cleavage or cytochrome c release by the inhibition of caspase activity linking these events. NO inhibited the capacity of purified caspase-3 to cleave recombinant Bcl-2. Both Bcl-2 cleavage and cytochrome c release were inhibited in tumor necrosis factor alpha- and actinomycin D-treated MCF-7 cells exposed to NO donors. The NO-mediated inhibition of Bcl-2 cleavage and cytochrome c release occurred in association with an inhibition of apoptosis and caspase-3-like activation. Thus, NO suppresses a key step in the positive feedback amplification of apoptotic signaling by preventing Bcl-2 cleavage and cytochrome c release.

Apoptosis↗

PubMed1998

Nitric oxide prevents IL-1beta and IFN-gamma-inducing factor (IL-18) release from macrophages by inhibiting caspase-1 (IL-1beta-converting enzyme).

Procytokine processing by caspase-1 is required for the maturation and release of IL-1beta and IFN-gamma-inducing factor (IGIF) (or IL-18) from activated macrophages (Mphi). Nitric oxide (NO) has emerged as a potent inhibitor of cysteine proteases. Here, we tested the hypothesis that NO regulates cytokine release by inhibiting IL-1beta-converting enzyme (ICE) or caspase-1 activity. Activated RAW264.7 cells released four to five times more IL-1beta, but not TNF-alpha, in the presence of the NO synthase inhibitor N(G)-monomethyl-L-arginine. Stimulated peritoneal Mphi from wild-type mice (inducible NO synthase (iNOS)+/+) also released more IL-1beta if exposed to N(G)-monomethyl-L-arginine, whereas Mphi from iNOS knockout mice (iNOS-/-) did not. Inhibition of NO synthesis in stimulated RAW264.7 cells also resulted in a threefold increase in intracellular caspase-1 activity. The NO donor S-nitroso-N-acetyl-DL-penicillamine inhibited caspase-1 activity in cells as well as the activity of purified recombinant caspase-1 and also prevented the cleavage of pro-IL-1beta and pro-IGIF by recombinant caspase-1. The inhibition of caspase-1 by NO was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. An in vivo role for the regulation of caspase-1 by NO was established in iNOS knockout animals, which exhibited significantly higher plasma levels of IL-1beta and IFN-gamma than their wild-type counterparts at 10 h following LPS injection. Taken together, these data indicate that NO suppresses IL-1beta and IGIF processing by inhibiting caspase-1 activity, providing evidence for a unique role for induced NO in regulating IL-1beta and IGIF release.

Animals↗

PubMed1998

Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice.

High concentrations of nitric oxide (NO) cause DNA damage and apoptosis in many cell types. Thus, regulation of NO synthase (NOS) activity is essential for minimizing effects of cytotoxic and genotoxic nitrogen oxide species. We have shown previously that NO-induced p53 protein accumulation down-regulates basal and cytokine-modulated inducible NOS (NOS2) expression in human cells in vitro. To further characterize the feedback loop between NOS2 and p53, we have investigated NO production, i.e., urinary nitrate plus nitrite excretion, and NOS2 expression in homozygous p53 knockout (KO) mice. We report here that untreated p53 KO mice excreted 70% more nitrite plus nitrate than mice with wild-type (wt) p53. NOS2 protein expression was constitutively detected in the spleen of untreated p53 KO mice, whereas it was undetectable in the spleen of wt p53 controls. Upon treatment with heat-inactivated Corynebacterium parvum, urinary nitrite plus nitrate excretion of p53 KO mice exceeded that of wt controls by approximately 200%. C. parvum treatment also induced p53 accumulation in the liver. Splenectomy reduced the NO output of C. parvum-treated p53 KO mice but not of wt p53 controls. Although NO production and NOS2 protein expression were increased similarly in KO and wt p53 mice 10 days after injection of C. parvum, NOS2 expression returned to baseline levels only in wt p53 controls while remaining up-regulated in p53 KO mice. These genetic and functional data indicate that p53 is an important transrepressor of NOS2 expression in vivo and attenuates excessive NO production in a regulatory negative feedback loop.

Animals↗

PubMed1998

Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene.

The human inducible nitric oxide synthase (iNOS) gene is overexpressed in a number of human inflammatory diseases. Previously, we observed that the human iNOS gene is transcriptionally regulated by cytokines and demonstrated that the cytokine-responsive regions are upstream of -3.8 kilobase pairs (kb). Therefore, the purpose of this study was to further localize the functional enhancer elements and to assess the role of the transcription factor NF-kappaB in both human liver (AKN-1) and human lung (A549) epithelial cell lines. The addition of NF-kappaB inhibitors significantly suppressed cytokine-stimulated iNOS mRNA expression and NO synthesis, indicating that NF-kappaB is involved in the induction of the human iNOS gene. Analysis of the first 4.7 kb of the 5'-flanking region demonstrated basal promoter activity and failed to show any cytokine-inducible activity. However, promoter constructs extending to -5.8 and -7.2 kb revealed 2-3-fold and 4-5-fold induction, respectively, in the presence of cytokines. DNA sequence analysis from -3.8 to -7.2 kb identified five putative NF-kappaB cis-regulatory transcription factor binding sites upstream of -4.7 kb. Site-directed mutagenesis of these sites revealed that the NF-kappaB motif at -5.8 kb is required for cytokine-induced promoter activity, while the sites at -5.2, -5.5, and -6.1 kb elicit a cooperative effect. Electromobility shift assays using a site-specific oligonucleotide and nuclear extracts from cells stimulated with cytokine-mixture, tumor necrosis factor-alpha or interleukin-1beta, but not interferon-gamma, exhibited inducible DNA binding activity for NF-kappaB. These data indicate that NF-kappaB activation is required for cytokine induction of the human iNOS gene and identifies four NF-kappaB enhancer elements upstream in the human iNOS promoter that confer inducibility to tumor necrosis factor-alpha and interleukin-1beta.

Base Sequence↗

PubMed1998

Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock.

Resuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N6-(iminoethyl)-L-lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor kappaB and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions.

Animals↗

PubMed1998

Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer.

Most evidence indicates that nitric oxide plays a role in normal wound repair; however, involvement of inducible nitric oxide synthase (iNOS) has not been established. Experiments were carried out to determine the requirement for iNOS in closing excisional wounds. Wound closure was delayed by 31% in iNOS knockout mice compared with wild-type animals. An identical delay in wound closure was observed in wild-type mice given a continuous infusion of the partially selective iNOS inhibitor N6-(iminoethyl)-L-lysine. Delayed wound healing in iNOS-deficient mice was completely reversed by a single application of an adenoviral vector containing human iNOS cDNA (AdiNOS) at the time of wounding. Reverse transcription PCR identified iNOS mRNA expression in wild-type mice peaking 4-6 d after wounding, and confirmed expression of human iNOS in the adenoviral vector containing human iNOS cDNA-treated animals. These results establish the key role of iNOS in wound closure, and suggest a gene therapy strategy to improve wound healing in iNOS-deficient states such as diabetes, and during steroid treatment.

3T3 Cells↗

PubMed1998

Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression.

An increased expression of nitric oxide synthase (NOS) has been observed in human colon carcinoma cell lines as well as in human gynecological, breast, and central nervous system tumors. This observation suggests a pathobiological role of tumor-associated NO production. Hence, we investigated NOS expression in human colon cancer in respect to tumor staging, NOS-expressing cell type(s), nitrotyrosine formation, inflammation, and vascular endothelial growth factor expression. Ca2+-dependent NOS activity was found in normal colon and in tumors but was significantly decreased in adenomas (P < 0.001) and carcinomas (Dukes' stages A-D: P < 0.002). Ca2+-independent NOS activity, indicating inducible NOS (NOS2), is markedly expressed in approximately 60% of human colon adenomas (P < 0.001 versus normal tissues) and in 20-25% of colon carcinomas (P < 0.01 versus normal tissues). Only low levels were found in the surrounding normal tissue. NOS2 activity decreased with increasing tumor stage (Dukes' A-D) and was lowest in colon metastases to liver and lung. NOS2 was detected in tissue mononuclear cells (TMCs), endothelium, and tumor epithelium. There was a statistically significant correlation between NOS2 enzymatic activity and the level of NOS2 protein detected by immunohistochemistry (P < 0.01). Western blot analysis of tumor extracts with Ca2+-independent NOS activity showed up to three distinct NOS2 protein bands at Mr 125,000-Mr 138,000. The same protein bands were heavily tyrosine-phosphorylated in some tumor tissues. TMCs, but not the tumor epithelium, were immunopositive using a polyclonal anti-nitrotyrosine antibody. However, only a subset of the NOS2-expressing TMCs stained positively for 3-nitrotyrosine, which is a marker for peroxynitrite formation. Furthermore, vascular endothelial growth factor expression was detected in adenomas expressing NOS2. These data are consistent with the hypothesis that excessive NO production by NOS2 may contribute to the pathogenesis of colon cancer progression at the transition of colon adenoma to carcinoma in situ.

Adenoma↗

PubMed1998

G-CSF instillation into rat lungs mediates neutrophil recruitment, pulmonary edema, and hypoxia.

Activated neutrophils (PMN) have been implicated in the pathogenesis of adult respiratory distress syndrome (ARDS). Granulocyte colony-stimulating factor (G-CSF) is essential for PMN production and activation of PMN functions. We have recently shown that levels of G-CSF mRNA in a rat model of hemorrhagic shock correlated with severity of shock, PMN infiltration, pulmonary edema, and hypoxia. To determine whether increased tissue levels of G-CSF contribute to PMN recruitment and PMN-mediated injury, we instilled G-CSF into the lungs by intratracheal injection. Animals treated with G-CSF became hypoxic, hypocapnic, and alkalotic and demonstrated increased BAL fluid cellularity compared with control animals. The wet-to-dry ratio increased significantly after G-CSF instillation and peaked at 12 h. Histological examination of the lungs from G-CSF-treated rats revealed marked edema and increased PMN within the interstitium and alveoli. These results indicate that the presence of G-CSF alone in the lung can lead to recruitment of PMN, lung injury, and impaired pulmonary function, suggesting that local production of G-CSF may contribute to the development of lung damage and possibly ARDS in the setting of resuscitated hemorrhagic shock.

Acute Disease↗

PubMed1998

Roles of nitric oxide in surgical infection and sepsis.

Recent advances in nitric oxide (NO) research have begun to elucidate the roles of NO in sepsis and infection. Although adequate levels of NO production are necessary to preserve perfusion and carry out cytoprotective functions in sepsis, overproduction appears to contribute to hemodynamic instability and tissue damage. These observations have led to the development of strategies to inhibit NO synthesis or scavenge excess NO in patients with septic shock. Local expression of the inducible NO synthase also has antimicrobial functions. The combination of NO with superoxide forms peroxynitrite which participates in bacterial killing in the peritoneal cavity. The capacity of red blood cells and hemoglobin to remove NO most likely accounts for the adjuvant effect of blood in peritonitis. This review will summarize the pathobiology of NO in surgical sepsis and infection.

Animals↗

PubMed1998

Activation of STAT proteins in the lung of rats following resuscitation from hemorrhagic shock.

Hemorrhagic shock (HS) initiates a series of inflammatory processes, including the production of proinflammatory cytokines at critical sites such as the lung. We have previously shown that granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) mRNA are produced in the lungs of rats subjected to resuscitated HS and that both the ischemic and reperfusion phases of resuscitated HS were required. G-CSF and IL-6 activate STAT (signal transducers and activators of transcription) proteins which may sustain the inflammatory response that follows resuscitation in HS. We tested the hypothesis that STAT proteins are activated in the lungs of rats subjected to resuscitated HS and examined the factors contributing to their activation including duration of shock and duration of resuscitation. Sprague-Dawley rats were subjected to compensated (66.1 +/- 1.1 min) or decompensated (157.3 +/- 2.3 min) HS (mean arterial pressure 40 mmHg) followed by resuscitation and sacrifice at 4 or 8 h. The amount of activated Stat3 was increased 2.3- to 7-fold compared with sham control animals in all four experimental groups of resuscitated HS. Levels of Stat3 activation increased with increase in duration of shock but did not demonstrate differences at the 4 or 8 h time point of killing. These results indicate that resuscitated HS results in the activation of the intracellular signaling cascade that includes that activation of STAT proteins driven by cytokines such as G-CSF and IL-6.

Acute-Phase Proteins↗