Predictive value of quick Sepsis-Related Organ Failure Scores following sepsis-related Medical Emergency Team calls: a retrospective cohort study.

We conducted a cohort study of adult ward patients who had a Medical Emergency Team (MET) call triggered by confirmed or suspected sepsis in an Australian tertiary centre to assess the predictive utility of systemic inflammatory response syndrome (SIRS) and quick Sepsis-Related Organ Failure Assessment (qSOFA) scores for 28-day mortality over a 12-month period. Sepsis was the causative aetiology in 970 MET calls for 646 patients with a mean age of 68 years and median Charlson Comorbidity score (CCS) of 3.0. Four hundred and seven (63%) patients had microbiological identification of a causative organism with 35 (9%) demonstrating multi-drug resistance. The 28-day mortality rate was 22%. Independent risk factors for 28-day mortality included age (incidence rate ratio [IRR] 1.038; P <0.001) and CCS (IRR 1.102; P <0.001). qSOFA positive patients had a three-fold risk of 28 day mortality compared to those who were negative (IRR 3.15; P=0.02). Both the SIRS and qSOFA score had poor sensitivity (86% versus 62%, respectively) for mortality as a sole diagnostic tool and should be investigated as part of a multiparameter panel within a large prospective study.

Influence of inflammation and nitric oxide upon platelet aggregation following deposition of diesel exhaust particles in the airways.

BACKGROUND AND PURPOSE: Exposure to nanoparticulate pollution has been implicated in platelet-driven thrombotic events such as myocardial infarction. Inflammation and impairment of NO bioavailability have been proposed as potential causative mechanisms. It is unclear, however, whether airways exposure to combustion-derived nanoparticles such as diesel exhaust particles (DEP) or carbon black (CB) can augment platelet aggregation in vivo and the underlying mechanisms remain undefined. We aimed to investigate the effects of acute lung exposure to DEP and CB on platelet activation and the associated role of inflammation and endothelial-derived NO. EXPERIMENTAL APPROACH: DEP and CB were intratracheally instilled into wild-type (WT) and eNOS-/- mice and platelet aggregation was assessed in vivo using an established model of radio-labelled platelet thromboembolism. The underlying mechanisms were investigated by measuring inflammatory markers, NO metabolites and light transmission aggregometry. KEY RESULTS: Platelet aggregation in vivo was significantly enhanced in WT and eNOS-/- mice following acute airways exposure to DEP but not CB. CB exposure, but not DEP, was associated with significant increases in pulmonary neutrophils and IL-6 levels in the bronchoalveolar lavage fluid and plasma of WT mice. Neither DEP nor CB affected plasma nitrate/nitrite concentration and DEP-induced human platelet aggregation was inhibited by an NO donor. CONCLUSIONS AND IMPLICATIONS: Pulmonary exposure to DEP and subsequent platelet activation may contribute to the reports of increased cardiovascular risk, associated with exposure to airborne pollution, independent of its effects on inflammation or NO bioavailability.

Drugs Affecting TRP Channels.

Chronic obstructive pulmonary disease (COPD) and asthma are both common respiratory diseases that are associated with airflow reduction/obstruction and pulmonary inflammation. Whilst drug therapies offer adequate symptom control for many mild to moderate asthmatic patients, severe asthmatics and COPD patients symptoms are often not controlled, and in these cases, irreversible structural damage occurs with disease progression over time. Transient receptor potential (TRP) channels, in particular TRPV1, TRPA1, TRPV4 and TRPM8, have been implicated with roles in the regulation of inflammation and autonomic nervous control of the lungs. Evidence suggests that inflammation elevates levels of activators and sensitisers of TRP channels and additionally that TRP channel expression may be increased, resulting in excessive channel activation. The enhanced activity of these channels is thought to then play a key role in the propagation and maintenance of the inflammatory disease state and neuronal symptoms such as bronchoconstriction and cough. For TRPM8 the evidence is less clear, but as with TRPV1, TRPA1 and TRPV4, antagonists are being developed by multiple companies for indications including asthma and COPD, which will help in elucidating their role in respiratory disease.

The role of the inflammasome in fibrotic respiratory diseases.

Fibrotic respiratory diseases severely disrupt lung function and currently have an extremely poor prognosis. This is attributable to the limited amount of treatment options available, in part due to our lack of understanding of the mechanisms driving disease pathogenesis. Although the majority of cases appear to be idiopathic, a number of factors are known to cause pulmonary fibrosis, such as the inhalation of silica crystals (silicosis), asbestos fibers (asbestosis) and certain drugs such as bleomycin. Evidence suggests that the inhalation of such substances can induce the formation of the NLRP3 inflammasome; a multimeric protein complex responsible for the activation of caspase-1 and maturation of the proinflammatory cytokines IL-1b and IL-18. Moreover, data suggests that inhibition of the inflammasome activation pathway and/or inflammasome-mediated cytokines can attenuate the fibrotic response in in vitro and in vivo models of disease. In this review, we discuss the evidence suggesting that the NLRP3 inflammasome plays an important role in the pathogenesis of fibrotic respiratory diseases, and the potential mechanisms by which activation of the NLRP3 inflammasome may occur. It is possible that fibrotic respiratory diseases with a known cause may share a common mechanism with idiopathic pulmonary fibrosis, providing possible strategies for future drug therapies.

Transient receptor potential (TRP) channels in the airway: role in airway disease.

Over the last few decades, there has been an explosion of scientific publications reporting the many and varied roles of transient receptor potential (TRP) ion channels in physiological and pathological systems throughout the body. The aim of this review is to summarize the existing literature on the role of TRP channels in the lungs and discuss what is known about their function under normal and diseased conditions. The review will focus mainly on the pathogenesis and symptoms of asthma and chronic obstructive pulmonary disease and the role of four members of the TRP family: TRPA1, TRPV1, TRPV4 and TRPM8. We hope that the article will help the reader understand the role of TRP channels in the normal airway and how their function may be changed in the context of respiratory disease.

Beta(2)-agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway.

beta(2)-Adrenoceptor agonists are the most effective bronchodilators currently available, and are used for symptom management in asthmatics. However, whether beta(2)-agonists are also antitussive is controversial. Identifying an antitussive role for beta(2)-agonists and dissecting the possible mechanism of action may help to explain the inconsistencies in the clinical literature and lead to the development of novel therapeutic agents. The aim of the present study was to determine whether or not beta(2)-agonists attenuate the tussive response in guinea pig and human models, and, if so, to identify the mechanism(s) involved. Depolarisation of vagal sensory nerves (human and guinea pig) was assessed as an indicator of sensory nerve activity. Cough was measured in a conscious guinea pig model. A beta(2)-agonist, terbutaline, dose-dependently inhibited the cough response to tussive agents in conscious guinea pigs. Terbutaline and another beta(2)-agonist, fenoterol, blocked sensory nerve activation in vitro. Using these mechanistic models, it was established that beta(2)-agonists suppress the tussive response via a nonclassical cyclic adenosine monosphosphate-dependent pathway that involves the activation of protein kinase G and, subsequently, the opening of large-conductance calcium-activated potassium channels. In conclusion, beta(2)-adrenoceptor agonists are antitussive, and this property occurs due to a direct inhibition of sensory nerve activation. These findings may help to explain the confusion that exists in the clinical literature, and could be exploited to identify novel therapies for the treatment of cough, which is a significant unmet medical need.

House dust mite induces direct airway inflammation in vivo: implications for future disease therapy?

House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. HDM can evoke a direct, nonallergic inflammatory reaction in vitro. We aimed to determine whether this apparent nonallergic, inflammatory response can be observed in a more complex in vivo setting. Vehicle, Alum or HDM (Dermatophagoides pteronyssinus 5 microg, i.p. with Alum) sensitised Brown-Norway rats were challenged intratracheally with vehicle (saline), HDM (Der p 10 microg) or heat-inactivated HDM on day 21. Lung function changes and the associated inflammatory response were evaluated. Tissue and bronchoalveolar lavage from Alum sensitised Der p challenged animals exhibited strong eosinophilia and neutrophilia associated with an early release of pro-inflammatory cytokines (interleukin-13 and 1beta, eotaxin and thymus and activation-regulated chemokine). This response was not attenuated by removal of HDM-associated protease activity. Interestingly, the vehicle sensitised group (no Alum) lacked this inflammatory response. HDM allergen evokes nonallergic airways inflammation with an inflammatory profile similar to that of the asthmatic airway. This response, independent of the protease activity of the HDM extract, appeared to be linked to prior administration of the adjuvant Alum and the subsequent increase in total immunoglobulin E. This finding could have important implications in the development of future asthma therapies.

Modulation of cholinergic contractions of airway smooth muscle by cathinone: potential beneficial effects in airway diseases.

Infusion of khat leaves is an African traditional remedy used to treat airway diseases. The beneficial effects of khat are thought to be due to the activity of its main active component, cathinone. Cathinone inhibited electric field stimulation-induced acetylcholine release and the contractions of smooth muscle, which could be responsible for the beneficial effects seen in airway disease. The mechanism of action of this natural product appears to be via the activation of both pre-junctional alpha(2) adrenergic and 5-hydroxytryptamine 7 receptors. The present novel study describes how cathinone modulates airway tone, and may go some way to explaining the traditional use of khat as a remedy for the alleviation of respiratory disease symptoms. In conclusion, cathinone may have beneficial effects in airway diseases with heightened cholinergic tone. There is some rationale for follow-up of these observations, given previous experience of other traditional remedies being developed for therapeutic use.

Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways.

BACKGROUND AND PURPOSE: Sensory nerves regulate central and local reflexes such as airway plasma protein leakage, bronchoconstriction and cough. Sensory nerve activity may be enhanced during inflammation such that these protective effects become exacerbated and deleterious. Cannabinoids are known to inhibit airway sensory nerve function. However, there is still controversy surrounding which receptor is involved in eliciting these effects. EXPERIMENTAL APPROACH: We have adopted a pharmacological approach, including using a novel, more selective CB(2) receptor agonist, GW 833972A (1000-fold selective CB(2)/CB(1)), and receptor selective antagonists to investigate the inhibitory activity of cannabinoids on sensory nerve activity in vitro and in vivo in guinea-pig models of cough and plasma extravasation. KEY RESULTS: GW 833972A inhibited capsaicin-induced depolarization of the human and guinea-pig and prostaglandin E(2) (PGE(2)) and hypertonic saline-induced depolarization of the guinea-pig isolated vagus nerve in vitro. GW 833972A also inhibited citric acid-induced cough but not plasma extravasation in the guinea-pig and this effect was blocked by a CB(2) receptor antagonist. CONCLUSIONS AND IMPLICATIONS: This confirms and extends previous studies highlighting the role of CB(2) receptors in the modulation of sensory nerve activity elicited both by the exogenous ligands capsaicin and hypertonic saline but also by endogenous modulators such as PGE(2) and low pH stimuli. These data establish the CB(2) receptor as an interesting target for the treatment of chronic cough.

Utility of exhaled nitric oxide as a noninvasive biomarker of lung inflammation in a disease model.

There is a great deal of interest in developing less invasive markers for monitoring airway inflammation and the effect of possible novel anti-inflammatory therapies that may take time to impact on disease pathology. Exhaled nitric oxide (eNO) has been shown to be a reproducible, noninvasive indicator of the inflammatory status of the airway in the clinic. The aim of the present study was to determine the usefulness of measuring eNO as a marker of the anti-inflammatory impact of glucocorticoid and an inhibitor of kappaB kinase-2 (IKK-2) inhibitor 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), in a pre-clinical model of airway inflammation. Rats were given vehicle, budesonide or TPCA-1 prior to exposure to lipopolysaccharide, previously shown to induce an increase in eNO and airway neutrophilia/eosinophilia. Comparison of the effect of the two compounds on inflammatory components demonstrated a significant correlation between the impact on eNO and inflammatory cell burden in the airway. The current study demonstrates the usefulness of profiling potential disease-modifying therapies on exhaled nitric oxide levels and the way in which an effect on this noninvasive biomarker relates to effects on pathological parameters such as lung cellularity. Information from studies such as the current one would suggest that the measurement of exhaled nitric oxide has potential for monitoring inflammatory status in lung tissue.

Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-kappaB-independent mechanism.

Consumption of a naturally occurring polyphenol, resveratrol, in particular through drinking moderate amounts of red wine, has been suggested to be beneficial to health. A plethora of in vitro studies published demonstrate various anti-inflammatory actions of resveratrol. The aim of this research was to determine whether any of these anti-inflammatory effects translate in vivo in a rodent model of LPS induced airway inflammation. Resveratrol reduced lung tissue neutrophilia to a similar magnitude as that achieved by treatment with budesonide. This was associated with a reduction in pro-inflammatory cytokines and prostanoid levels. Interestingly, the reduction did not appear to be due to an impact on NF-kappaB activation or the expression of the respective genes as suggested by various in vitro publications. These results suggest that resveratrol may possess anti-inflammatory properties via a novel mechanism. Elucidation of this mechanism may lead to potential new therapies for the treatment of chronic inflammation.

PPAR-gamma agonists as therapy for diseases involving airway neutrophilia.

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor super-family. Previously, the present authors have shown that PPAR-gamma agonists inhibit the release of inflammatory cell survival factors and induce apoptosis in vitro. The aim of this study was to determine the effect of two structurally different PPAR agonists in an in vivo model of lipopolysaccharide (LPS)-induced airway inflammation. Mice were treated with PPAR agonists, rosiglitazone or SB 219994, prior to exposure to aerosolised LPS, and the extent of airway inflammation was assessed 3 h later. In these experiments, the PPAR ligands inhibited LPS-induced airway neutrophilia and associated chemoattractants/survival factors (keratinocyte-derived chemokine and granulocyte-colony stimulating factor) in the mouse lung. The present authors postulate that if a peroxisome proliferator-activated receptor agonist has the same effect in man, and neutrophils are important in the progression of respiratory diseases, such as chronic obstructive pulmonary disease, then this class of compounds could be a potential therapy. Furthermore, several peroxisome proliferator-activated receptor-gamma agonists have been shown to be clinically effective for the treatment of type II diabetes, suggesting that any benefit of peroxisome proliferator-activated receptor-gamma ligands in the progression of respiratory diseases, which may involve airway neutrophilia, could be explored relatively quickly.

Evidence that the anti-spasmogenic effect of the beta-adrenoceptor agonist, isoprenaline, on guinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase.

1. The spasmolytic and anti-spasmogenic activity of beta-adrenoceptor agonists on airways smooth muscle is thought to involve activation of the cyclic AMP/cyclic AMP-dependent protein kinase (PKA) cascade. Here we have tested the hypothesis that PKA mediates the anti-spasmogenic activity of isoprenaline and other cyclic AMP-elevating agents in guinea-pig isolated trachea by utilizing a number of cell permeant cyclic AMP analogues that act as competitive 'antagonists' of PKA. 2. Anion-exchange chromatography of guinea-pig tracheae resolved two peaks of PKA activity that corresponded to the type I ( approximately 5%) and type II ( approximately 93%) isoenzymes. 3. Pre-treatment of tracheae with zardaverine (30 microM), vasoactive intestinal peptide (VIP) (1 microM) and the non-selective activator of PKA, Sp-8-CPT-cAMPS (10 microM), produced a non-parallel rightwards shift in the concentration-response curves that described acetylcholine (ACh)-induced tension generation. The type II-selective PKA inhibitor, Rp-8-CPT-cAMPS (300 microM), abolished this effect. 4. Pre-treatment of tracheae with Sp-8-Br-PET-cGMPS (30 microM) produced a non-parallel rightwards shift of the concentration-response curves that described ACh-induced tension generation. The selective cyclic GMP-dependent protein kinase (PKG) inhibitor, Rp-8-pCPT-cGMPS (300 microM), abolished this effect. 5. Pre-treatment of tracheae with isoprenaline (1 microM) produced a 10 fold shift to the right of the ACh concentration-response curve by a mechanism that was unaffected by Rp-8-Br-cAMPS (300 microM, selective inhibitor of type I PKA), Rp-8-CPT-cAMPS (300 microM) and Rp-8-pCPT-cGMPS (300 microM). 6. We conclude that the anti-spasmogenic activity of Sp-8-CPT-cAMPS, zardaverine and VIP in guinea-pig trachea is attributable to activation of the cyclic AMP/PKA cascade whereas isoprenaline suppresses ACh-induced contractions by a mechanism(s) that is independent of PKA and PKG.

Role of p38 MAP kinase in LPS-induced airway inflammation in the rat.

We investigated the effect of the p38 kinase inhibitor SB 203580 on airway inflammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 significantly inhibited (ED(50)=15.8 mg kg(-1)) plasma levels of TNF-alpha in rats challenged with LPS (1.5 mg kg(-1), i.p.). Aerosolized LPS induced a peak in TNF-alpha levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL) fluid at the 2 h time point. Furthermore, the 4 h time point was associated with the peak in IL-1beta levels and the initial plateau of neutrophilia observed in the BAL fluid. SB 203580 (100 mg kg(-1)), had no effect on peak TNF-alpha levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100 mg kg(-1)) significantly reduced both TNF-alpha levels and neutrophilic inflammation. However, the BAL fluid from rats pre-treated with either compound significantly inhibited TNF-alpha release from cultured human monocytes 18 h after LPS treatment (83.6 and 44.5% inhibition, respectively). Alternatively, SB 203580 (100 mg kg(-1)) produced dose-related inhibition of BAL IL-1beta levels (67.5% inhibition, P<0.01) and BAL neutrophilia (45.9% inhibition, P<0.01) 4 h after LPS challenge. P38 protein was present in lung tissue and the level of expression was not affected by LPS treatment. P38 kinase appears to be involved in the release of IL-1beta and the sustained neutrophilic response in the BAL fluid. This data may suggest a role for p38 inhibitors in the treatment of airway inflammatory diseases in which neutrophilia is a feature of the lung pathology.

Chronic systemic administration of salmeterol to rats promotes pulmonary beta(2)-adrenoceptor desensitization and down-regulation of G(s alpha).

1. The aim of the present study was to examine the effects of chronic infusion of the long-acting agonist salmeterol on pulmonary beta(2)-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular basis of any altered state. 2. Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E(2) (PGE(2)), given acutely by the intravenous route, to protect against ACh-induced bronchoconstriction when compared to rats treated identically with vehicle. 3. beta(1)- and beta(2)-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associated with impaired salmeterol- and PGE(2)-induced cyclic AMP accumulation ex vivo. 4. Three variants of G(s alpha) that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol. 5. The activity of cytosolic, but not membrane-associated, G-protein receptor-coupled kinase was elevated in the lung of salmeterol-treated rats when compared to vehicle-treated animals. 6. The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh-induced bronchoconstriction was short-acting (t(off) approximately 45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation. 7. These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary G(s)-coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane-associated G(s alpha). The short-acting nature of salmeterol, when administered systemically, and the reduction in beta-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective beta-adrenoceptor agonist.

The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

Mediator involvement in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitized Brown Norway rats.

1. To determine which mediators are involved in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitised Brown Norway rats we investigated the effect of a histamine H(1) receptor antagonist, mepyramine, a 5-HT receptor antagonist, methysergide, and a cys-leukotriene-1 receptor antagonist, montelukast. 2. Ovalbumin at 1 mg kg(-1) i.v. caused a significant increase in microvascular leakage in the airways and at 3 mg kg(-1) i.v. caused a significant increase in airways resistance. 3. Histamine (1 mg kg(-1) i.v.), 5-HT (0.1 mg kg(-1) i.v.) and leukotriene D(4) (LTD(4), 50 microg kg(-1) i.v.) caused a significant increase in microvascular leakage in the airways. 4. Mepyramine (1 mg kg(-1) i.v.), methysergide (0.1 mg kg(-1) i.v.), or montelukast (30 mg kg(-1) i.v.) inhibited histamine, 5-HT or LTD(4) -induced microvascular leakage respectively. 5. Methysergide (0.1 mg kg(-1) i.v.) reduced ovalbumin-induced microvascular leakage in the trachea and at 0.3 mg kg(-1) i.v. inhibited bronchospasm (38 and 58%, respectively). Montelukast (30 mg kg(-1) p.o.) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (78%) and inhibited ovalbumin-induced bronchospasm (50%). Mepyramine (3 mg kg(-1) i.v.) had no effect on ovalbumin-induced leakage or bronchospasm. 6. A combination of all three compounds (mepyramine, methysergide and montelukast) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (70 - 78%) and almost completely inhibited bronchospasm (92%). 7. Antigen-induced bronchospasm appears to equally involve the activation of 5-HT and cys-leukotriene-1 receptors whereas ovalbumin-induced microvascular leakage appears to be predominantly mediated by cys-leukotriene-1 receptors.

Effect of endothelin antagonists, including the novel ET(A) receptor antagonist LBL 031, on endothelin-1 and lipopolysaccharide-induced microvascular leakage in rat airways.

1. The effect of the novel ET(A) receptor antagonist LBL 031 and other selective and mixed endothelin receptor antagonists on endothelin-1 (ET-1)-induced and lipopolysaccharide (LPS)-induced microvascular leakage was assessed in rat airways. 2. Intravenously administered ET-1 (1 nmole kg(-1)) or LPS (30 mg kg(-1)) caused a significant increase in microvascular leakage in rat airways when compared to vehicle treated animals. 3. Pre-treatment with the selective ET(A) receptor antagonists, LBL 031 or PD 156707, or the mixed ET(A/B) receptor antagonist, bosentan (each at 30 mg kg(-1)), reduced ET-1-induced leakage to baseline levels. ET-1-induced leakage was not reduced by pre-treatment with the ET(B) selective antagonist BQ 788 (3 mg kg(-1)). 4. Pre-treatment with the selective ET(A) receptor antagonist, LBL 031 (0.1 mg kg(-1)) or PD 156707 (10 mg kg(-1)), or the mixed ET(A/B) receptor antagonist, bosentan (30 mg kg(-1)), reduced LPS-induced leakage by 54, 48 and 59% respectively. LPS-induced leakage was not affected by pre-treatment with the ET(B) selective antagonist BQ 788 (3 mg kg(-1)). 5. The data suggests that ET-1-induced microvascular leakage in the rat airway is ET(A) receptor mediated and that part of the increase induced by LPS may be due to the actions of ET-1. Therefore, a potent ET(A) receptor selective antagonist, such as LBL 031, may provide a suitable treatment for inflammatory diseases of the airways, especially those involving LPS and having an exudative phase, such as the septic shock-induced adult respiratory distress syndrome.

Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat.

Tumour necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) have been implicated in the pathogenesis of asthma. The p38 kinase inhibitor, SB 203580 inhibits TNF-alpha and IL-1beta production in vitro and in vivo. In this study the effect of SB 203580 on allergen-induced airway TNF-alpha production and inflammatory cell recruitment was investigated in sensitized Brown Norway rats. The allergen-induced increase in bronchoalveolar lavage (BAL) TNF-alpha was inhibited by SB 203580 at every dose tested (10 - 100 mg kg(-1), p.o.). In contrast, neither ovalbumin-induced eosinophilia or neutrophilia were inhibited by SB 203580 (10 - 100 mg kg(-1), p.o.). In conclusion, SB 203580 inhibits BAL TNF-alpha production by 95% without inhibiting either antigen-induced airway eosinophilia or neutrophilia. This data suggests that either the residual TNF-alpha is sufficient to drive allergen-induced inflammatory cell recruitment into the lung or that TNF-alpha is not involved in allergen-induced inflammatory cell recruitment.