Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis.
Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis
A population survey of 1000 7 year old children found a significant excess of wheeze among children whose homes were reported to be mouldy (odds ratio 3 70, 95% confidence limits 2-22, 6-15).The airborne mould flora was quantified by repeated volumetric sampling during the winter in three rooms of the homes of 88 children. All of these had previously completed spirometric tests before and after a six minute free running exercise challenge. Total airborne mould counts varied from 0 to 41 000 colony forming units (CFU)/m3, but were generally in the range 50-1500 CFU/m3, much lower than the concentrations found outdoors in summer. The principal types of fungi identified are all known to be common out of doors, and most were found on at least one occasion in most of the homes. Median and geometric mean total mould counts were not related to reports of visible mould in the home, or to a history of wheeze in the index child. The heterogeneous group of non-sporing fungi (mycelia sterilia) were the only airborne fungi present at significantly higher concentrations in the homes of wheezy children (geometric mean 2-1 v 0 7 CFU/m3. A non-significant increase in total mould counts was observed in the homes of children with a
This report of an association with a polymorphic site within the IL-1 locus and AS suggests that genes other than B27 may well be involved in the pathogenesis of AS.
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