Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.

BACKGROUND: Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis. METHODS: Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated. RESULTS: Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice. CONCLUSIONS: In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.

A deep learning approach to student registered nurse anesthetist (SRNA) education.

OBJECTIVES: This manuscript describes the application of deep learning to physiology education of Student Registered Nurse Anesthetists (SRNA) and the benefits thereof. A strong foundation in physiology and the ability to apply this knowledge to challenging clinical situations is crucial to the successful SRNA. Deep learning, a well-studied pedagogical technique, facilitates development and long-term retention of a mental knowledge framework that can be applied to complex problems. Deep learning requires the educator to facilitate the development of critical thinking and students to actively learn and take responsibility for gaining knowledge and skills. METHODS: We applied the deep learning approach, including flipped classroom and problem-based learning, and surveyed SRNA students (n=127) about their learning experience. RESULTS: Survey responses showed that the majority of students favored the deep learning approach and thought it advanced their critical thinking skills. CONCLUSIONS: SRNAs reported that their physiology knowledge base and critical thinking benefited from the use of the deep learning strategy.

Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.

Arrestins have been shown to regulate numerous G protein-coupled receptors (GPCRs) in studies employing receptor/arrestin overexpression in artificial cell systems. Which arrestin isoforms regulate which GPCRs in primary cell types is poorly understood. We sought to determine the effect of ß-arrestin-1 or ß-arrestin-2 inhibition or gene ablation on signaling and function of multiple GPCRs endogenously expressed in airway smooth muscle (ASM). In vitro [second messenger (calcium, cAMP generation)], ex vivo (ASM tension generation in suspended airway), and in vivo (invasive airway resistance) analyses were performed on human ASM cells and murine airways/whole animal subject to ß-arrestin-1 or -2 knockdown or knockout (KO). In both human and murine model systems, knockdown or KO of ß-arrestin-2 relative to control missense small interfering RNA or wild-type mice selectively increased (40-60%) ß2-adrenoceptor signaling and function. ß-arrestin-1 knockdown or KO had no effect on signaling and function of ß2-adrenoceptor or numerous procontractile GPCRs, but selectively inhibited M3 muscarinic acetylcholine receptor signaling (∼50%) and function (∼25% ex vivo, >50% in vivo) without affecting EC50 values. Arrestin subtypes differentially regulate ASM GPCRs and ß-arrestin-1 inhibition represents a novel approach to managing bronchospasm in obstructive lung diseases.

Genetic Deletion of ß-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model.

ß-Arrestin-2 (ßarr2) is a ubiquitously expressed cytosolic protein that terminates G protein-coupled receptor signaling and transduces G protein-independent signaling. We previously showed that mice lacking ßarr2 do not develop an asthma phenotype when sensitized to, and challenged with, allergens. The current study evaluates if an established asthma phenotype can be mitigated by deletion of ßarr2 using an inducible Cre recombinase. We sensitized and challenged mice to ovalbumin (OVA) and demonstrated that on Day (d) 24 the allergic asthma phenotype was apparent in uninduced ßarr2 and wild-type (WT) mice. In a second group of OVA-treated mice, tamoxifen was injected on d24 to d28 to activate Cre recombinase, and OVA aerosol challenge was continued through d44. The asthma phenotype was assessed using lung mechanics measurements, bronchoalveolar lavage cell analysis, and histological assessment of mucin and airway inflammation. Compared with their respective saline-treated controls, OVA-treated WT mice and mice expressing the inducible Cre recombinase displayed a significant asthma phenotype at d45. Whereas tamoxifen treatment had no significant effect on the asthma phenotype in WT mice, it inhibited ßarr2 expression and caused a significant reduction in airway hyper-responsiveness (AHR) in Cre-inducible mice. These findings suggest that ßarr2 is actively required for perpetuation of the AHR component of the allergic asthma phenotype. Our finding that ßarr2 participates in the perpetuation of AHR in an asthma model means that targeting ßarr2 may provide immediate and potentially long-term relief from daily asthma symptoms due to AHR irrespective of inflammation.

ß-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway.

Proteinase-Activated receptor-2 (PAR(2)), a G-protein-coupled Receptor, activated by serine proteinases, is reported to have both protective and proinflammatory effects in the airway. Given these opposing actions, both inhibitors and activators of PAR(2) have been proposed for treating asthma. PAR(2) can signal through two independent pathways: a ß-arrestin-dependent one that promotes leukocyte migration, and a G-protein/Ca(2+) one that is required for prostaglandin E(2) (PGE(2)) production and bronchiolar smooth muscle relaxation. We hypothesized that the proinflammatory responses to PAR(2) activation are mediated by ß-arrestins, whereas the protective effects are not. Using a mouse ovalbumin model for PAR(2)-modulated airway inflammation, we observed decreased leukocyte recruitment, cytokine production, and mucin production in ß-arrestin-2(-/-) mice. In contrast, PAR(2)-mediated PGE(2) production, smooth muscle relaxation, and decreased baseline airway resistance (measures of putative PAR(2) "protective" effects) were independent of ß-arrestin-2. Flow cytometry and cytospins reveal that lung eosinophil and CD4 T-cell infiltration, and production of IL-4, IL-6, IL-13, and TNFα, were enhanced in wild-type but not ß-arrestin-2(-/-) mice. Using the forced oscillation technique to measure airway resistance reveals that PAR(2) activation protects against airway hyperresponsiveness by an unknown mechanism, possibly involving smooth muscle relaxation. Our data suggest that the PAR(2)-enhanced inflammatory process is ß-arrestin-2 dependent, whereas the protective anticonstrictor effect of bronchial epithelial PAR(2) may be ß-arrestin independent.

The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse.

Hydrogen sulfide (H2S) has been reported to be involved in the signaling of the inflammatory response; however, there are differing views as to whether it is pro- or anti-inflammatory. In this study, we sought to determine whether endogenously synthesized H2S via cystathionine-γ-lyase (CSE) plays a pro- or anti-inflammatory role in caerulein-induced pancreatitis. To investigate this, we used mice genetically deficient in CSE to elucidate the function of CSE in caerulein-induced acute pancreatitis. We compared the inflammatory response and tissue damage of wild-type (WT) and CSE knockout (KO) mice following 10 hourly administrations of 50 µg/kg caerulein or saline control. From this, we found that the CSE KO mice showed significantly less local pancreatic damage as well as acute pancreatitis-associated lung injury compared with the WT mice. There were also lower levels of pancreatic eicosanoid and cytokines, as well as reduced acinar cell NF-κB activation in the CSE KO mice compared with WT mice. Additionally, in WT mice, there was a greater level of pancreatic CSE expression and sulfide-synthesizing activity in caerulein-induced pancreatitis compared with the saline control. When comparing the two saline-treated control groups, we noted that the CSE KO mice showed significantly less pancreatic H2S-synthesizing activity relative to the WT mice. These results indicate that endogenous H2S generated by CSE plays a key proinflammatory role via NF-κB activation in caerulein-induced pancreatitis, and its genetic deletion affords significant protection against acute pancreatitis and associated lung injury.

Allosteric modulator potentiates ß2AR agonist-promoted bronchoprotection in asthma models.

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled ß2-adrenergic receptor (ß2AR) agonists (ß2-agonists) promote - with limited efficacy - bronchodilation in asthma. All ß2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a ß2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on ß2AR-mediated bronchoprotection. Consistent with our findings using human ß2ARs, Cmpd-6 allosterically potentiated ß2-agonist binding to guinea pig ß2ARs and downstream signaling of ß2ARs. In contrast, Cmpd-6 had no such effect on murine ß2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced ß2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated ß2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced ß2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of ß2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.

Vertical sleeve gastrectomy associates with airway hyperresponsiveness in a murine model of allergic airway disease and obesity.

Introduction: Asthma is a chronic airway inflammatory disease marked by airway inflammation, remodeling and hyperresponsiveness to allergens. Allergic asthma is normally well controlled through the use of beta-2-adrenergic agonists and inhaled corticosteroids; however, a subset of patients with comorbid obesity experience resistance to currently available therapeutics. Patients with asthma and comorbid obesity are also at a greater risk for severe disease, contributing to increased risk of hospitalization. Bariatric surgery improves asthma control and airway hyperresponsiveness in patients with asthma and comorbid obesity, however, the underlying mechanisms for these improvements remain to be elucidated. We hypothesized that vertical sleeve gastrectomy (VSG), a model of metabolic surgery in mice, would improve glucose tolerance and airway inflammation, resistance, and fibrosis induced by chronic allergen challenge and obesity. Methods: Male C57BL/6J mice were fed a high fat diet (HFD) for 13 weeks with intermittent house dust mite (HDM) allergen administration to induce allergic asthma, or saline as control. At week 11, a subset of mice underwent VSG or Sham surgery with one week recovery. A separate group of mice did not undergo surgery. Mice were then challenged with HDM or saline along with concurrent HFD feeding for 1-1.5 weeks before measurement of lung mechanics and harvesting of tissues, both of which occurred 24 hours after the final HDM challenge. Systemic and pulmonary cytokine profiles, lung histology and gene expression were analyzed. Results: High fat diet contributed to increased body weight, serum leptin levels and development of glucose intolerance for both HDM and saline treatment groups. When compared to saline-treated mice, HDM-challenged mice exhibited greater weight gain. VSG improved glucose tolerance in both saline and HDM-challenged mice. HDM-challenged VSG mice exhibited an increase in airway hyperresponsiveness to methacholine when compared to the non-surgery group. Discussion: The data presented here indicate increased airway hyperresponsiveness in allergic mice undergoing bariatric surgery.

Stakeholder-Guided Development of Dialysis Vascular Access Education Materials.

Background: Initiating hemodialysis via an arteriovenous (AV) access is considered best practice for most patients. Despite the well-recognized advantages of AV access, 80% of US patients start hemodialysis with a catheter. Limited patient knowledge about vascular access, among other factors, may play a role in this high rate. We used iterative stakeholder input to develop novel, mixed media vascular access education materials and evaluated their preliminary acceptability. Methods: We conducted preliminary focus groups and interviews with key stakeholders to assess patient vascular access understanding and elicit perspectives on existing education materials. We then used stakeholder input to inform initial development and iterative updates to the content and design of an animated video and complementary brochure. Video development (scripting, storyboarding, animation) was guided by an evidence-based framework and two health behavior change models. We assessed acceptability of the completed materials with patients and medical providers/personnel via interviews. Results: Overall, 105 stakeholders participated in education materials development and review (80 patients/care partners, 25 medical providers/personnel). Preliminary qualitative work included 52 patients/care partners and 16 providers/personnel; video development included 28 patients/care partners and nine providers/personnel. The video script, storyboards, and animation underwent 14, four, and nine stakeholder-guided iterations, respectively. Responsive changes included aesthetic modifications, technical updates, and content additions (e.g., HD circuit, access self-monitoring, enhanced patient testimonials). The final 18-minute video and complementary brochure define vascular access types, describe care processes, outline potential complications, and address common patient concerns. Interviews with 28 patients/care partners and nine providers/personnel from diverse geographic regions revealed preliminary acceptability of, and enthusiasm for, the materials by patients and providers. Conclusions: In collaboration with key stakeholders, we developed mixed media vascular access education materials that were well-received by patients and providers. Preliminary findings suggest that the materials are promising to improve vascular access understanding among patients.

Plasma cytokine profiles in preprotachykinin-A knockout mice subjected to polymicrobial sepsis.

During the course of polymicrobial sepsis, a range of pro- and antiinflammatory cytokines are produced by the host immune system. Successful recovery from sepsis involves striking a balance between these counteracting cytokines. We herein investigated the circulating cytokine profiles in preprotachykinin-A knockout (PPTA(-/-)) mice, which have been found to be protected significantly against microbial sepsis, by employing multiplexed bead-based suspension arrays for the measurement of 18 plasma cytokines. Four sets of PPTA(-/-) and wild-type mice, each with six mice, were subjected to cecal ligation and puncture-induced sepsis or a sham procedure and were killed at 1, 5, 8 and 24 h post surgery. The cytokine profiles revealed, rather interestingly, that both pro- and antiinflammatory cytokines were elevated in the knockout group in response to a septic challenge. The higher systemic levels of both pro- and antiinflammatory cytokines in PPTA(-/-) septic mice was similar to the increase that we observed earlier in lung tissue of PPTA(-/-) mice after induction of sepsis. Thus, elevated levels of both pro- and antiinflammatory mediators may act simultaneously and help to resolve the infectious assault at the early stages of sepsis without excessively damaging the host tissue in PPTA(-/-) mice. In addition, our results underline the importance of comprehensive clinical analysis of multiple biomarkers to provide a better prognostic tool.

Substance P in polymicrobial sepsis: molecular fingerprint of lung injury in preprotachykinin-A-/- mice.

Deletion of mouse preprotachykinin-A (PPTA), which encodes mainly for neuropeptide substance P, has been shown to protect against lung injury and mortality in sepsis. This study explored microarray-based differential gene expression profiles in mouse lung tissue 8 h after inducing microbial sepsis and the effect of PPTA gene deletion. A range of genes differentially expressed (more than two-fold) in microarray analysis was assessed, comparing wild-type and PPTA-knockout septic mice with their respective sham controls, and the data were further validated. Genetic deletion of substance P resulted in a significantly different expression profile of genes involved in inflammation and immunomodulation after the induction of sepsis, compared with wild-type mice. Interestingly, apart from the various proinflammatory mediators, the antiinflammatory cytokine interleukin-1 receptor antagonist gene (IL1RN) was also elevated much more in PPTA(-/-) septic mice. In addition, semiquantitative RT-PCR analysis supported the microarray data. The microarray data imply that the elevated levels of inflammatory gene expression in the early stages of sepsis in PPTA-knockout mice are possibly aimed to resolve the infection without excessive immunosuppression. As scientists are divided over the effects of pro- and antiinflammatory mediators in sepsis, it seems prudent to define the status depending on a complete genome profile. This is the first report exploring pulmonary gene expression profiles using microarray analysis in PPTA-knockout mice subjected to cecal ligation and puncture-induced sepsis and providing additional biological insight into the protection received against lung injury and mortality.

Dialysis Access: At the Intersection of Policy, Innovation, and Clinical Care.

The Advancing American Kidney Health executive order aims to reduce the incidence of end-stage kidney disease, promote home dialysis therapies, increase the number of kidney transplants, and encourage innovation in new technologies, evidence-based practice, and early detection of kidney disease. Improvements in dialysis access care are essential to the success and expansion of this program, and to being able to provide high-quality, cost-efficient care to this patient population. Specifically, the need for expanded access to home dialysis will require surgeons and interventionalists to become proficient and trained in peritoneal dialysis catheter placement and for the referral process to be streamlined to accommodate the increased interest in this modality. In addition, new technologies, namely percutaneous fistula creation, bioengineered vessels, and a variety of interventions to reduce arteriovenous stenosis, will hopefully allow for timely and durable vascular access options that will support implementation of the executive order.

Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia.

Endotoxemia is a life-threatening, inflammatory condition that involves multiple organ injury and dysfunction. Preprotachykinin-A (PPT-A) gene products, substance P (SP), and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products on multiple organ injury in LPS-induced endotoxemia, endotoxemia was induced by LPS administration (10 mg/kg, i.p.) in PPT-A gene-deficient mice (PPTA(-/-)) and the wild-type (WT) control mice (PPT-A+/+). I.p. administration of LPS to WT mice caused a significant increase in circulating levels of SP as well as in liver, lung, and kidney. PPT-A gene deletion significantly protected against liver, pulmonary, and renal injury following LPS-induced endotoxemia, as evidenced by tissue myeloperoxidase activities, plasma alanine aminotransferase, aspartate aminotransferase levels, and histological examination. Furthermore, PPT-A(-/-) mice had significantly attenuated chemokines, proinflammatory cytokines, and adhesion molecule levels in the liver, lung, and kidney. These results show that PPT-A gene products are critical proinflammatory mediators in endotoxemia and the associated multiple organ injury. In addition, the data suggest that deletion of the PPT-A gene protected mice against organ damage in endotoxemia by disruption in neutrophil recruitment.

Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats.

OBJECTIVES: The effects of the flavonoid rutin on the anticoagulant activity of oral warfarin and the protein binding and pharmacokinetics of its enantiomers were investigated in rats. METHODS: A single dose of racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or on day 5 of an 8-day oral regimen of rutin, 1 g/kg daily. RESULTS: Rutin reduced the anticoagulant effect of racemic warfarin, evident as a 31% reduction in the area under the prothrombin complex activty-time curve (P < 0.05). KEY FINDINGS: Rutin had no apparent effect on pre-treatment baseline blood coagulation. It enhanced the in-vitro serum protein binding of S- and R-warfarin (reflected by 40% and 26% reductions in unbound fraction, respectively), and thus restricted distribution by 33 and 21%, respectively. Treatment with rutin significantly decreased the elimination half-life of S-warfarin by 37% as a result of the 69% increase in unbound clearance of the S-enantiomer. This effect was attributed to a significant 77% increase in the unbound formation clearance of the overall oxidative and reductive metabolites, and an increase in the unbound renal clearance of the more potent S-enantiomer of warfarin. CONCLUSIONS: Concurrent rutin administration is likely to reduce the anticoagulant effect of racemic warfarin, reflecting a significant decrease in the elimination half-life of the more potent S-enantiomer.

Methods to Investigate the Roles for ß-Arrestin-2 in Allergic Inflammatory Airway Disease.

Spatial and temporal control of gene expression using cre/loxP technology is a major methodological advance for biomedical research. The ability to alter gene expression after an in vivo disease model has been established and allows researchers the opportunity to examine the impact of that gene on the perpetuation of a disease, a mechanistic insight that is arguably more therapeutically relevant than developmental mechanisms.We used the cre/LoxP technology in mice to show that ß-arrestin-2, a gene previously shown to be required for the development of the asthma phenotype, is also required for the perpetuation of, at least, the airway hyperresponsiveness characteristic of that phenotype. Here we describe stepwise methods for the activation of the cre-loxP technology and induction of murine allergic inflammatory airway disease. We comment on the unanticipated problems encountered, which we speculate were a result of interactions between the allergen and ß-arrestin-2 gene (Arrb2) regulation and the effect of tamoxifen on the asthma phenotype. The issues encountered here may be generally applicable to cre/loxP utilization in inflammatory disease models, especially if the gene of interest is associated with the inflammatory cascade.

Therapeutic Potential of Targeting ß-Arrestin.

ß-arrestins are multifunctional proteins that modulate heptahelical 7 transmembrane receptors, also known as G protein-coupled receptors (GPCRs), a superfamily of receptors that regulate most physiological processes. ß-arrestin modulation of GPCR function includes termination of G protein-dependent signaling, initiation of ß-arrestin-dependent signaling, receptor trafficking to degradative or recycling pathways, receptor transactivation, transcriptional regulation, and localization of second messenger regulators. The pleiotropic influence ß-arrestins exert on these receptors regulates a breadth of physiological functions, and additionally, ß-arrestins are involved in the pathophysiology of numerous and wide-ranging diseases, making them prime therapeutic targets. In this review, we briefly describe the mechanisms by which ß-arrestins regulate GPCR signaling, including the functional cellular mechanisms modulated by ß-arrestins and relate this to observed pathophysiological responses associated with ß-arrestins. We focus on the role for ß-arrestins in transducing cell signaling; a pathway that is complementary to the classical G protein-coupling pathway. The existence of these GPCR dual signaling pathways offers an immense therapeutic opportunity through selective targeting of one signaling pathway over the other. Finally, we will consider several mechanisms by which the potential of dual signaling pathway regulation can be harnessed and the implications for improved disease treatments.

Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis.

Earlier work from our laboratory has suggested a role for the neuropeptide substance P (SP) in inducing lung injury in sepsis. In that study, mice lacking the preprotachykinin-A gene, which encodes for SP, were protected against lung injury in sepsis. To further substantiate the role of SP in sepsis and to study its mechanism, we have evaluated the effect of SR140333, a SP receptor antagonist, on lung injury in sepsis, which was induced in male Swiss mice by cecal ligation and puncture (CLP). Sham-operated animals received the same surgical procedure, except CLP. Vehicle or SR140333 (1 mg/kg, s.c.) was administered to CLP mice 30 min before or 1 h after the CLP. Eight hours after surgery, lung tissue was collected and analyzed for myeloperoxidase (MPO) activity, chemokines, cytokines, and adhesion molecules. The CLP procedure alone caused a significant increase in the lung levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, E- and P-selectin, and MPO activity when compared with sham-operated mice. SR140333 injected 30 min before or 1 h after CLP significantly attenuated the increased lung MPO activity and levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, and E- and P-selectin compared with CLP-operated mice injected with the vehicle. Histological evaluation of the lung sections further supported the beneficial effect of SR140333 on lung inflammation. Therefore, SP receptor antagonism can be a potential therapeutic target in polymicrobial sepsis, and this effect is brought about via reduction in leukocyte recruitment.

Treatment with antileukinate, a CXCR2 chemokine receptor antagonist, protects mice against acute pancreatitis and associated lung injury.

Acute pancreatitis is a common, and as yet incurable, clinical condition, the incidence of which has been increasing over recent years. Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that treatment with a neutralizing antibody against CINC, a CXC chemokine, protects rats against acute pancreatitis-associated lung injury. The hexapeptide antileukinate (Ac-RRWWCR-NH2) is a potent inhibitor of binding of CXC chemokines to the receptors (CXCR2). This study aims to evaluate the effect of treatment with antileukinate on acute pancreatitis and the associated lung injury in mice. Acute pancreatitis was induced in adult male Swiss mice by hourly intra-peritoneal injections of caerulein (50 microg/kg/h) for 10 h. Antileukinate (52.63 mg/kg, s.c.) was administered to mice either 30 min before or 1 h after starting caerulein injections. Severity of acute pancreatitis was determined by measuring plasma amylase, pancreatic water content, pancreatic myeloperoxidase (MPO) activity, pancreatic macrophage inflammatory protein-2 (MIP-2) levels and histological examination of sections of pancreas. A rise in lung MPO activity and histological evidence of lung injury in lung sections was used as criteria for pancreatitis-associated lung injury. Treatment with antileukinate protected mice against acute pancreatitis and associated lung injury, showing thereby that anti-chemokine therapy may be of value in this condition.

Hydrogen sulfide acts as a pro-inflammatory mediator in rheumatic disease.

OBJECTIVE: Hydrogen sulfide (H2 S) is a gaseous mediator produced in the body. In experimental models, endogenously produced H2 S has been shown to have pro-inflammatory effects. The aim of this study was to investigate whether H2 S is present in three common rheumatic diseases, rheumatoid arthritis (RA), gout and osteoarthritis (OA) and to determine if H2 S levels correlate with disease activity. METHODS: Patients with RA, gout, OA, and healthy controls (n = 30 each) were recruited. Plasma and where possible, synovial fluid (SF), were obtained. Levels of H2 S and interleukin-6 (IL-6) (a known inflammatory marker as a positive control) were determined and assessed for their relationship with disease activity. RESULTS: SF-H2 S levels were significantly elevated in both RA and gout when compared to respective plasma levels. Plasma levels of H2 S were not different from those in healthy controls in patients with either RA or gout. In OA, plasma levels of H2 S were significantly elevated compared to healthy controls. In RA, SF-H2 S levels correlated with Disease Activity Score (DAS)-28 and tender joint count. CONCLUSION: H2 S is present in the joint and acts as a pro-inflammatory mediator in rheumatic diseases. H2 S may be a novel therapeutic target for these conditions.

Neurogenic inflammation in acute pancreatitis.

Acute pancreatitis is a clinical condition whose incidence has increased over the past few years. The exact mechanism of its development is not yet clear. Substance P, the proinflammatory neuropeptide, has a role in the initiation of neurogenic inflammation. Substance P and its receptor neurokinin-1 receptor (NK-1R) are involved in the development of local as well as systemic inflammation in acute pancreatitis. This editorial focuses on the role of substance P and its receptors in the development of acute pancreatitis.