KIS protects against adverse vascular remodeling by opposing stathmin-mediated VSMC migration in mice

Vascular proliferative diseases are characterized by VSMC proliferation and migration. Kinase interacting with stathmin (KIS) targets 2 key regulators of cell proliferation and migration, the cyclin-dependent kinase inhibitor p27^Kip1 and the microtubule-destabilizing protein stathmin. Phosphorylation of p27^Kip1 by KIS leads to cell-cycle progression, whereas the target sequence and the physiological relevance of KIS-mediated stathmin phosphorylation in VSMCs are unknown. Here we demonstrated that vascular wound repair in KIS^–/– mice resulted in accelerated formation of neointima, which is composed predominantly of VSMCs. Deletion of KIS increased VSMC migratory activity and cytoplasmic tubulin destabilizing activity, but abolished VSMC proliferation through the delayed nuclear export and degradation of p27^Kip1. This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of KIS-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation. Downregulation of stathmin in KIS^–/– VSMCs fully restored the phenotype, and stathmin-deficient mice demonstrated reduced lesion formation in response to vascular injury. These data suggest that KIS protects against excessive neointima formation by opposing stathmin-mediated VSMC migration and that VSMC migration represents a major mechanism of vascular wound repair, constituting a relevant target and mechanism for therapeutic interventions.     

Isoniazid protects mice against endotoxin lethality without influencing tumor necrosis factor synthesis and release.

Treatment of NMRI mice with isoniazid (INH; 25 mg/kg) intraperitoneally induced significant protection when it was injected before or after a lethal intravenous challenge with endotoxin. The INH preparation used was not contaminated with endotoxin. Tumor necrosis factor (TNF) was not elevated in sera from NMRI mice 2 h after the injection of INH. INH did not influence TNF synthesis or release determined in human monocytes in vitro. Therefore, it is concluded that the protective effect of INH against lethal endotoxin is not due to a suppressive effect of INH on TNF production.     

Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus

Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin beta receptor-Ig (LTbetaR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTbetaR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.     

Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the sigma1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and sigma1 receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.     

Maternal exposure to farming environment protects offspring against allergic diseases by modulating the neonatal TLR-Tregs-Th axis

Background

As the development of urbanization in China, the morbidity of allergic disease rise up prominently even in children, which may be partially associated with the excessively clean environment. It has been reported that common microorganism in rural environment shows protective effects on allergic disease by modulating TLRs-Tregs/Th cell axis. But the mechanism of this protection still needs to be elucidated in detail. We investigated the effects of maternal exposure to farming environment on the neonatal innate immune system, especially on the TLR-Treg-Th (Th1, Th2, Th9, and Th17) axis, in the Jilin province of China.

Methods

Eighty-four non-farming and 42 farming pregnant women were recruited. Endotoxins and glucans in dust from the living rooms of the pregnant mothers were measured. Cord blood mononuclear cells were challenged with phytohemagglutinin, lipopolysaccharide, or peptidoglycan. Proliferative response of lymphocyte was measured by 3H-TdR incorporation methods, CD4?+?CD25?+?FOXP3?+?T cells percentage was assessed with flow cytometry, Tregs specific genes (FOXP3, LAG3, GITR, CTLA-4 and TGF-β) and TLR2, TLR4 genes expression were detected by RT-PCR, specific cytokines of Th1, Th2, Th9, Th17 and Tregs were measured with flow cytometer, suppressive capacity of Tregs was tested by culturing with effector cells in vitro, and TLR2/4 gene polymorphism was detected.

Results

Higher endotoxin content was observed in the living rooms of the farming mothers. Compared with that in the non-farming group, in farming neonatal CBMCs, lymphocyte proliferation declined; the IFN-γ/IL-13 ratio increased; and the quantity of Tregs and gene expression of FOXP3, GITR, CTLA4 and TLR2 increased significantly (P?<?0.05). Isolated Tregs suppressed the proliferation of effector T cells and IL-13 production more strongly in vitro (P?=?0.04, 0.03, respectively), and the TLR2 polymorphism affected FOXP3 expression and IFN-γ and IL-13 production.

Conclusions

Maternal exposure to farming affected the quantity and function of neonatal Tregs upon stimulation with PPG and LPS, which partly contributed to reducing the risk for allergic diseases in the offspring. The results of our study will lay the theoretical foundation for allergic disease prevention in early life.

     

Persistent reversal of tolerance to anticonvulsant effects and GABAergic subsensitivity by a single exposure to benzodiazepine antagonist during chronic benzodiazepine administration

The persistence of benzodiazepine antagonists in reversing neuronal and behavioral tolerance during chronic diazepam exposure was examined in rodents by investigating the time course for antagonist-induced alterations in iontophoretic sensitivity to gamma-aminobutyric acid on dorsal raphe neurons and the re-emergence of anticonvulsant efficacy to bicuculline-induced seizures. In these studies, exposure to Ro15-1788 resulted in the persistent reversal of GABAergic subsensitivity and restoration of anticonvulsant actions of diazepam despite the continued presence of diazepam in the rats. Reversal of tolerance appears to persist for up to 7 days after a single exposure to benzodiazepine antagonists.     

LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor

Leukocyte cell–derived chemotaxin 2 (LECT2) is a multifunctional cytokine and reduced plasma levels were found in patients with sepsis. However, precise functions and mechanisms of LECT2 remain unclear. The aim of the present study was to determine the role of LECT2 in modulating immune responses using mouse sepsis models. We found that LECT2 treatment improved outcome in mice with bacterial sepsis. Macrophages (MΦ), but not polymorphonuclear neutrophils, mediated the beneficial effect of LECT2 on bacterial sepsis. LECT2 treatment could alter gene expression and enhance phagocytosis and bacterial killing of MΦ in vitro. CD209a was identified to specifically interact with LECT2 and mediate LECT2-induced MΦ activation. CD209a-expressing MΦ was further confirmed to mediate the effect of LECT2 on sepsis in vivo. Our data demonstrate that LECT2 improves protective immunity in bacterial sepsis, possibly as a result of enhanced MΦ functions via the CD209a receptor. The modulation of MΦ functions by LECT2 may serve as a novel potential treatment for sepsis.Sepsis is defined as infection with systemic inflammatory reaction syndrome and can be the result of injury, burn, pancreatitis, surgery, and other disease states (Levy et al., 2003). More than half of sepsis cases are caused by infection with bacteria, among which the most important pathogens include Escherichia coli and Pseudomonas aeruginosa (Annane et al., 2005). Sepsis remains the leading cause of death in critically ill patients worldwide, despite modern advances in critical care. Macrophages (MΦ) are the key component of the innate immune system, forming a bridge between innate and adaptive immunity by producing a myriad of cytokines, and phagocytosing and presenting antigens to the immune system, responses which are severely impaired in septic patients (Hotchkiss and Karl, 2003). Thus, MΦ are a potentially important therapeutic target in sepsis (Anderson et al., 2012).Leukocyte cell–derived chemotaxin 2 (LECT2) is a multifunctional factor originally identified as a neutrophil chemotactic protein (Yamagoe et al., 1996), consisting of 151 amino acids and three intramolecular disulfide bonds. It is produced in the liver and secreted into the blood. LECT2 is involved in many pathological conditions, such as renal amyloidosis (Benson et al., 2008), hepatocarcinogenesis (Ong et al., 2011), and severe liver injury (Saito et al., 2004). Most recently, plasma LECT2 levels were found to be down-regulated in septic patients (Ando et al., 2012), suggesting a relationship between LECT2 and sepsis. However, precise functions and mechanisms of LECT2 in sepsis remain unclear. C-type lectin receptors (CLRs) perform multiple functions in myeloid cells, including MΦ (Kang et al., 2003; Osorio and Reis e Sousa, 2011). CD209, pattern recognition receptors belonging to the CLR superfamily, can not only recognize exogenous carbohydrate ligands to provide innate resistance to microbial infection (Robinson et al., 2006) but also bind to endogenous self-ligands to maintain immune homeostasis (García-Vallejo and van Kooyk, 2009). For example, SIGN-R1(CD209b) in spleen MΦ can capture pneumococcal capsular polysaccharide to activate complement system through an unusual C3 activation pathway (Kang et al., 2006).In this study, we determined that LECT2 treatment improved survival in septic mice via the increased phagocytic ability, bactericidal activity, and beneficial cytokine production of MΦ. These effects were mediated through CD209a. Moreover, CD209a-expressing MΦ mediated the effect of LECT2 on sepsis. Collectively, our data suggest that LECT2 plays a potentially important role in MΦ activation and for the treatment of sepsis.     

Epitopic peptides with low similarity to the host proteome: towards biological therapies without side effects

Background: A structured analysis of the literature indicates that a low level of sequence similarity to the host proteome modulates the B cell epitope pool in the humoral immune response toward protein antigens. From a clinical point of view, low-similarity peptides might have strong repercussions for the rational development of peptide-based treatments for cancer, autoimmunity and infectious diseases. The most attractive feature of the similarity concept is that it appears to guarantee the highest specificity and lowest cross-reactivity when designing effective, safe and theoretically infallible (immuno)therapeutic tools. Objective/methods: This review describes the research pathway from protein- to peptide-based therapies. Results/conclusions: Using the breast-cancer-associated BRCA2 protein as a model, the principle of sequence uniqueness is defined as the rationale for a pharmacological platform that might yield improved results in both patient survival and quality of life.     

Lanoconazole, a new imidazole antimycotic compound, protects MAIDS mice against encephalitis caused by Cryptococcus neoformans

The protective effect of a new antifungal compound, lanoconazole, against Cryptococcus neoformans infection in C57BL/6 mice exposed to LP-BM5 murine leukaemia virus (MuLV) (MAIDS mice) was investigated. Mice were infected intratracheally with C. neoformans, strain 613D, 40 days after infection with LP-BM5 MuLV. They were treated orally with various doses of lanoconazole or with fluconazole 10 mg/kg (a positive control) once daily beginning 1 day after the fungal infection and continuing until the end of the experimental period. The number of C. neoformans cells in the lungs and brains of infected mice was determined. Lanoconazole and fluconazole had a similar inhibitory effect on the growth of C. neoformans in the brains and lungs of normal mice. Whereas lanoconazole inhibited the growth of C. neoformans in the brains and lungs of MAIDS mice, the pathogen grew in the brains of MAIDS mice treated with fluconazole. Lanoconazole reduced the number of C. neoformans in the brains of normal mice treated with a type 2 cytokine mixture, whereas fluconazole did not. A predominance of type 2 T-cell responses was demonstrated in MAIDS mice. Splenic T cells from MAIDS mice, but not those from normal mice, released interleukins 4 and 10 into the culture medium when they were stimulated with an anti-CD3 monoclonal antibody. These results suggest that lanoconazole may have the potential to inhibit the growth of C. neoformans in AIDS patients with a predominance of type 2 T-cell responses.     

Inhibition of proinflammatory cytokines by SCH79797, a selective protease-activated receptor 1 antagonist, protects rat kidney against ischemia-reperfusion injury

Renal ischemia-reperfusion injury (I/R) is the most common cause of acute renal failure. It is partially mediated by thrombin as it is attenuated by thrombin inhibition or deletion of its receptor protease-activated receptor 1 (PAR1). However, the role of PAR1 in renal I/R injury needs to be further elucidated. The present study investigated the effect of PAR1 antagonist, SCH79797 (SCH), on renal protection and downstream effectors involved. Male Wistar rats were pretreated with SCH (25 μg/kg i.p.) or vehicle, 15 min before 45 min of clamping of left renal pedicle after right nephrectomy. To investigate the involvement of phosphatidylinositol 3-kinase (PI3K)/Akt, a group of rats was subjected to pretreatment with an inhibitor of PI3K/Akt (LY 29004, 3 mg/kg i.p.) before renal ischemia and SCH treatment. A sham-operated group served as control and received saline. All rats were killed 24 h after reperfusion or sham operation, and blood samples collected and kidney tissues processed either for immunostaining and histological assessment or for biochemical analysis. SCH79797 markedly attenuated kidney damage histologically and by improving serum creatinine. Both plasma and protein expression of P selectin were markedly reduced as well as neutrophil infiltration, cytokine-induced neutrophil chemoattractant 1, and tumor necrosis factor α. These protective effects of blocking PAR1 receptor were abolished by preadministration of LY29004. These results suggest that PAR1 mediates renal I/R injury and that blocking PAR1 using SCH limits renal injury by an anti-inflammatory effect possibly signaling via PI3K/Akt.     

Evaluation of potential adverse health effects resulting from chronic domestic exposure to the organophosphate insecticide methyl parathion

Methyl parathion (MP) was used illegally to spray homes for insect control over approximately an 8-yr period. In an attempt to determine if there were any adverse health effects from this, health-screening evaluations were performed on 353 individuals living in homes that were illegally sprayed. The average subject spent 15.5 h a day in the home. Subjects from homes with high levels of MP (exposure group) were compared to controls that lived in homes with minimal or no MP. Subjects were aware of the levels of MP found in their homes and recall bias was likely. There were no significant differences in the symptoms reported or by the physician assessment of subacute or chronic toxicity between those in the exposure group and controls. No significant differences were found in growth and developmental evaluations. Three subjects were identified who most likely suffered acute toxicity from the initial exposure and were not appropriately diagnosed and treated. Cholinesterase determinations also did not differ between those in the exposure group and controls. When subjects from the exposure group were stratified by the level of MP in their home, those from homes with the highest levels appeared to have an increased likelihood of subacute toxicity and reported an increased number of neuropsychiatric symptoms (OR 2 for both evaluations).     

Psychological techniques for controlling the adverse side effects of cancer chemotherapy: findings from a decade of research.

Cancer patients receiving chemotherapeutic treatments often experience unpleasant side effects that compromise the quality of their life and may be so severe that they lead to suboptimal drug dosages, missed treatments, or even discontinuation of treatment. In recent years it has been discovered that some of these side effects result from maladaptive learning. This article reviews over 10 years of research conducted at Vanderbilt University on the prevention and treatment of these psychological side effects. This research includes the assessment of the efficacy of a behavioral relaxation technique, the exploration of procedures that make this intervention clinically practical for widespread application, research aimed at predicting which patients will and will not benefit from the intervention, and the comparison of this intervention to alternative treatment approaches. The review of this research generates four major conclusions and points to several important areas for future inquiry.     

Treatment of adverse effects of excessive phencyclidine exposure in rats with a minimal dose of monoclonal antibody

The range of medical effects and complications resulting from excessive use of drugs of abuse like phencyclidine (PCP) has hindered the development of effective medications. Drug-specific monoclonal antibodies (mAbs) provide an appealing medication approach since they can be selective for the drug, without concern for the sites of action of the drug. The use of mAb medications has been considered impractical because it is commonly believed that very large doses of mAb would be required to treat the adverse medical effects resulting from excessive drug use. In this study, a single dose of an anti-PCP mAb was found to significantly reduce the negative health impact of excessive, prolonged PCP treatment in rats (18 mg/kg/day for 2 weeks). The protective effects were mAb dose-dependent, and mAb doses as low as 1/100th the molar equivalent amount of the PCP body burden were effective at preventing PCP-induced deaths, reducing PCP-induced behaviors, reducing PCP brain concentrations, and improving the general health status of the animals. They also show that treatment with monoclonal antibody medications can have medically important outcomes without the need to neutralize the entire dose of the offending drug. These results could help establish the feasibility of using carefully designed monoclonal antibody medications to treat drug abuse and addiction, a chronic and re-occurring illness of the central nervous system.     

Long-term exposure to retrovirally expressed granulocyte-colony-stimulating factor induces a nonneoplastic granulocytic and progenitor cell hyperplasia without tissue damage in mice.

Murine marrow cells infected with a retroviral vector (MPZen) bearing a granulocyte-colony-stimulating factor (G-CSF) cDNA insert were transplanted into lethally irradiated recipients to study the effects of autocrine production of G-CSF in normal hemopoietic cells. Most animals remained healthy with no evidence of tissue damage throughout the observation period (4-30 wk) despite high circulating G-CSF levels (range 2,000-26,000,000 U/ml). A dramatic neutrophilic granulocytosis was observed in all hemopoietic tissues with neutrophilic infiltration occurring in the lung and liver. Spleen, peritoneal, and peripheral blood cellularity increased approximately three-, two-, and eightfold, respectively, but total bone marrow cell counts remained unchanged. Progenitor cell numbers granulocyte-macrophage colony-forming cell (GM-CFC), granulocyte colony-forming cell (G-CFC), burst-forming unit-erythroid (BFU-E), colony-forming unit-erythroid (CFU-E) and mixed colony-forming cells (Mix-CFC) were elevated between 10-100-fold in the spleen, peritoneal cavity, and peripheral blood, but were unaffected or slightly depressed in the marrow. No tumors developed in syngeneic recipients transplanted with bone marrow or spleen cells from such mice, confirming the nonneoplastic nature of the hyperplasia induced by chronic G-CSF stimulation. These experiments also indicated the stable integration of MPZen vectors in infected cells, as evident from the continuous expression of the inserted gene for at least 6 mo, and from the ability of infected stem cells from the primary recipients to express the gene in lethally irradiated secondary recipients.     

BRP,a polysaccharide fraction isolated from Boschniakia rossica,protects against galactosamine and lipopolysaccharide induced hepatic failure in mice

The aim of this study was to investigate the hepatoprotective effect of BRP, a polysaccharide fraction isolated from Boschniakia rossica, against galactosamine and lipopolysaccharide induced fulminant hepatic failure. Mice were injected with a single dose of galactosamine/lipopolysaccharide with or without pretreatment of BRP. Results showed marked reduction of hepatic necrosis, serum marker enzymes and levels of tumor necrosis factor-α and interleukin-6 in BRP pretreated mice when compared with galactosamine/lipopolysaccharide-challenged mice. Mice pretreated with BRP decreased the activation of caspases-3 and caspase-8, and showed a reduced level of DNA fragmentation of liver cells. BRP also reduced hepatic lipid peroxidation, increased potential of hepatic antioxidative defense system, and reduced hepatic nitric oxide level which was elevated by galactosamine/lipopolysaccharide injection. Immunoblot analysis showed down-regulation of inducible nitric oxide synthase and cyclooxygenase-2 proteins of liver tissues in BRP pretreated group when compared with galactosamine/lipopolysaccharide-challenged group. Furthermore, treatment with galactosamine/lipopolysaccharide markedly increased toll-like receptor 4, nuclear level of nuclear factor-κB, and phosphorylation of both extracellular signal-regulated kinase and c-Jun N-terminal kinase in liver tissues. However, these increases were attenuated by pretreatment with BRP. The results suggest that BRP alleviates galactosamine/lipopolysaccharide-induced liver injury by enhancing antioxidative defense system, suppressing inflammatory responses and reducing apoptotic signaling.     

Analgesic effects evoked by a CCR2 antagonist or an anti‐CCL2 antibody in inflamed mice

Chemokine CCL2, also known as monocyte chemoattractant protein‐1 (MCP‐1), is a molecule that in addition to its well‐established role in chemotaxis can also act as nociceptor sensitizer. The upregulation of this chemokine in inflamed tissues could suggest its involvement in inflammatory hypernociception. Thus, we have measured CCL2 levels in mice with acute or chronic inflammation due to the intraplantar (i.pl.) injection of carrageenan or complete Freund's adjuvant (CFA), respectively, and we have studied whether inflammatory hyperalgesia or allodynia could be attenuated by blocking CCR2 receptors or neutralizing CCL2 with an anti‐CCL2 antibody. A remarkable increase in CCL2 concentration was detected by ELISA in paw homogenates coming from carrageenan‐ or CFA‐inflamed mice, being its expression mainly localized in macrophages, as shown by immunohistochemical assays. The s.c. (0.3–3 mg/kg) or i.pl. (0.3–3 μg) administration of the CCR2 antagonist, RS 504393, dose dependently inhibited thermal hyperalgesia measured in acutely or chronically inflamed mice, whereas s.c. administration of this drug did not reduce inflammatory mechanical allodynia. Furthermore, the inhibition of inflammatory hyperalgesia after the administration of an anti‐CCL2 antibody (0.1–1 μg; i.pl.) suggests that CCL2 could be the endogenous chemokine responsible for CCR2‐mediated hyperalgesic effects. Besides, the acute administration of the highest antihyperalgesic dose of RS 504393 assayed did not reduce paw tumefaction or modify the presence of inflammatory cells. These results indicate that the blockade of the CCL2/CCR2 system can counteract inflammatory hyperalgesia, being this antinociceptive effect unrelated to a decrease in the inflammatory reaction.     

Managing cancer side effects to improve quality of life: a cancer psychoeducation program

This study aimed to develop and pilot test a community-based education program that addresses the prevention and management of the major side effects of cancer and its treatment according to a Patient Active Empowerment Model. This piloted program evaluated the health and quality of life outcomes for patients with cancer. The program was implemented through a half-day patient education conference. This conference included clinical information concerning disease and treatment-related side effects, an overview of treatment methods, information to help improve communication between the patient and healthcare team, education materials and experiences to empower patients and caregivers, and integration of specific mind-body techniques to strengthen key educational messages and reinforce the importance of side effect management. A total of 32 patients completed both the program and psychometric assessments on the day of the intervention and 30 days later. The participants were primarily white women with an average age of 57 years. Breast cancer was the most prevalent type of cancer experienced by the participants. The pilot results for this small sample showed that from baseline to follow-up evaluation, patients reported significant decreases in depressive symptoms and problems with work or other daily activities that resulted from emotional distress. Some improvements in health and well-being were greater for those who had not experienced fever or infection, those who had no children, and those who were working. Participants indicated that the program was useful in its ability to help them manage treatment side effects. Although the findings presented in this article are based only on a pilot program evaluation and a small sample, they do suggest that the program may be effective in educating patients about specific cancer side effects and empowering them to cope more effectively with their illness. Results showing that subgroups of individuals may have benefited more from the intervention provide important information about specific components of the program that may be particularly salient and potential changes that might be usefully implemented.     

Hydrazine sulfate protects D-galactosamine-sensitized mice against endotoxin and tumor necrosis factor/cachectin lethality: evidence of a role for the pituitary

In previously published studies, we had demonstrated that hydrazine sulfate pretreatment protected mice against the lethal effects of endotoxin and that this protection was accompanied by a sustained increase in hepatic phosphoenolpyruvate carboxykinase activity (Silverstein, R., C.A. Christoffersen, and D.C. Morrison. 1989. Infect. Immun. 57:2072). The same hydrazine sulfate pretreatment has now been found to protect mice against endotoxin in the D-galactosamine model with an increase in the endotoxin LD50 of approximately four orders of magnitude. Elimination of the pretreatment period, or administration of an additional dose of D-galactosamine at the time of hydrazine sulfate pretreatment, renders the mice refractory to the protection. Given the sensitivity of phosphoenolpyruvate carboxykinase regulation to several hormones, we investigated the possibility that protection may have been hormone mediated. In addition to determining the effect of hydrazine sulfate on the plasma levels of phosphoenolpyruvate carboxykinase regulating hormones, we have investigated the effects of hydrazine sulfate on endotoxin lethality in mice whose capacity to respond hormonally to external stimuli has been compromised by hypophysectomy. Our results show a significant enhancement in circulating levels of plasma corticosterone 30 min after hydrazine sulfate injection. Moreover, hypophysectomy results in a marked increase in sensitivity of mice to endotoxin challenge as well as an abrogation of the protection against endotoxin lethality mediated by hydrazine sulfate. Although hydrazine sulfate protection distinguishes between sensitivity brought on, individually, by D-galactosamine and by hypophysectomy, mice sensitized by both hypophysectomy and D-galactosamine are not protected against endotoxin lethality by hydrazine sulfate. We conclude that hydrazine sulfate protection against endotoxin lethality is endocrine dependent, with the available evidence implicating a pituitary/adrenal axis, with glucocorticoid involvement. In as much as D-galactosamine is known to act directly in the liver in disrupting protein synthesis, it is proposed that events in the liver are critical to the hydrazine sulfate-mediated protection against endotoxin and are possibly the target of the endocrine involvement. Hydrazine sulfate pretreatment also protects D-galactosamine-sensitized mice against the lethal effects of injected tumor necrosis factor/cachectin.     

Glucocorticoids as a novel approach to the treatment of disabling side effects of sodium stibogluconate

What is known and Objective: Intravenous sodium stibogluconate (SbV) is the mainstay of treatment for mucocutaneous leishmaniasis. Incidence of this disease is increasing in the UK, partly because of returning military personnel. SbV has a side effect profile that requires treatment interruption in up to 28% of patients. Side effects can be unpleasant and – in the case of QTc prolongation – dangerous. Case summary: A volunteer medical worker returning from Guatemala was diagnosed with mucocutaneous leishmaniasis. Because of previous renal problems, NSAIDs were contraindicated. Severe side effects of myalgia and arthralgia would have necessitated a treatment interruption, but a trial of prednisolone gave excellent symptomatic relief. The patient’s QTc, amylase and C‐reactive protein also fell following initiation of steroid treatment. The SbV treatment course was completed successfully. What is new and conclusion: This is the first reported case of the dangerous and disabling side effects of SbV being treated very effectively with glucocorticoids. Of note is the normalization of the apparently sodium stibogluconate–induced prolongation of the QTc interval. Further investigation into this potential beneficial effect is warranted.