Acute arthritis in man and dog after intrasynovial injection of sodium urate crystals
About: This article is published in The Lancet.The article was published on 1962-10-06. It has received 237 citations till now.
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TL;DR: It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.
Abstract: Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.
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TL;DR: Current knowledge of cell death and repair processes in the host and their importance to host defence and disease pathogenesis has only been appreciated relatively recently is reviewed.
Abstract: When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes - that is, it is part of normal physiological processes - then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.
1,626 citations
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TL;DR: Compared the pain producing activity of fatty acid hydroperoxides with that of high concentrations of acetylcholine, bradykinin, histamine and PGE1 on intradermal injection in man, the intensity of the pain induced was greater than that induced by the other agonists but for all except P GE1 the pain was transitory.
Abstract: THE importance of prostaglandins in inflammation has been emphasized by the discovery that aspirin-like anti-inflammatory drugs inhibit their synthesis1–3. The anti-inflammatory and anti-pyretic effects of this group of drugs could be explained on this basis1, but their analgesic properties could not, then, be firmly linked to inhibition of prostaglandin synthesis. This was because the only subjective effect reported on intradermal injection of prostaglandin was a sensation of warmth and a slight itching*, and on the blister base PGE2 (up to 100 µg/ml.) failed to produce pain5. Several reports now describe the pain-producing activity of prostaglandins infused i.v. and injected intramuscularly6–8 in man. Collier and Schneider have shown that PGE1 is the most powerful agent in producing writhing responses in mice9. Vane1 suggested that rabbit aorta contracting substance (RCS)10 which may be the unstable cyclic peroxide intermediate in the biosynthesis of prostaglandins11, may be involved in the production of pain in inflammation. I tried to test this hypothesis by comparing the pain producing activity of fatty acid hydroperoxides with that of high concentrations of acetylcholine, bradykinin, histamine and PGE1 on intradermal injection in man. The intensity of the pain induced by the hydroperoxides was greater than that induced by the other agonists but for all except PGE1 the pain was transitory. On testing subdermal infusions to mimic the continuous release of an endogenous mediator of pain, two important properties of E-type prostaglandins were revealed. First, they increase the pain sensitivity to chemical and mechanical stimulation. Second, their effects are cumulative and depend not only on their concentrations but also on the time of exposure. The term “pain” is used to denote the overt pain evoked chemically during the infusions; hyperalgesia is used when pain was elicited only by applying slight pressure on the infusion area. Studies were carried out in five male volunteers each of whom received a full explanation of the nature of the experiment before giving his consent. The experiments were double blind.
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TL;DR: Urate crystals have been noted in synovial fluid from gouty patients in the past, but this finding was believed to be infrequent and of little assistance to the clinician in his attempt to diagnose and treat the disease.
Abstract: Excerpt Urate crystals have been noted in synovial fluid from gouty patients in the past, but this finding was believed to be infrequent and of little assistance to the clinician in his attempt to ...
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