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D R Blake

Publications and source records attributed to D R Blake.

At least 199 records · Page 11Linked to original sources

Oxidants, joint inflammation and anti-inflammatory strategies.

In summary, we support the hypothesis that the rheumatoid knee is subjected to repeated hypoxic reperfusion injury. Moreover, we speculate that oxidative damage induced as a consequence of hypoxic reperfusion injury leads to the synthesis of intracellular stress proteins. In certain individuals this triggers an autoimmune response which might explain the persistance of the rheumatoid disease process. This gives scope for novel therapeutic approaches in the future development of anti-inflammatory agents.

Animals↗

Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis.

By means of antisera to cytoplasmic components of nerve fibres and neuropeptides which are known to be present in sensory or sympathetic nerves we have examined the distribution of both total and different types of nerve fibres in normal and inflamed human synovial tissue. Samples of synovia were obtained at surgery from five normal and five rheumatoid patients (age range 10-77 years). In order to map the overall neural innervation of the synovium, antiserum to the general neuronal marker protein gene product 9.5 was employed. Substance P and calcitonin gene-related peptide antisera were employed to identify sensory fibres and antisera to the C-flanking peptide of neuropeptide Y to distinguish sympathetic nerves. In normal synovium protein gene product 9.5-immunoreactive fibres were numerous, in particular, the vasculature was densely innervated. Free protein gene product 9.5-immunoreactive fibres were less numerous but were present in all synovia examined, and in many cases these extended to the intimal layer. Neuropeptide immunostaining was predominantly found in perivascular networks. Fibres immunoreactive for the C-flanking peptide of neuropeptide Y were exclusively located around blood vessels whereas free fibres were immunoreactive for substance P or calcitonin gene-related peptide. As with free protein gene product 9.5-immunoreactive fibres, fibres expressing substance P or calcitonin gene-related peptide immunoreactivity were often seen in the intimal cell layer. In rheumatoid arthritis a similar innervation to that seen in normal synovium was apparent in the deep tissue but fibres immunoreactive for protein gene product 9.5, the C-flanking peptide of neuropeptide Y, substance P or calcitonin gene-related peptide were not visible in the more superficial tissues or the intimal cell layer. In addition, immunostaining of neuropeptides in the deep tissue was weaker in the diseased tissues than in normal controls. The data unequivocally demonstrate that synovial tissues are richly innervated and confirm the presence of both sensory and sympathetic nerves. The absence of nerves which innervate the superficial synovium in rheumatoid arthritis might suggest that there is increased release of substance P, calcitonin gene-related peptide and the C-flanking peptide of neuropeptide Y, reducing the stores in the nerves to levels below that detectable by immunocytochemistry. However, since protein gene product 9.5-immunoreactive nerves were not seen in the inflamed tissue it is probable that synovial growth outflanks neural growth and consequently as the disease progresses neural structures become restricted to deeper tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

A model for desferrioxamine-induced retinopathy using the albino rat.

We describe a rat model of the ocular toxicity induced in patients by the iron chelator desferrioxamine (DFX). The functional integrity of the rat photoreceptor membrane is assessed by measurement of the electroretinogram b wave amplitude. Following single bolus doses of DFX (50, 100 and 150 mg), rats develop dose-related suppression of b wave amplitude within 48 h. Recovery takes place over the subsequent 14 days. This ocular damage is exacerbated by exposure to increased levels of white light and oxygen. Studies in this model also show that darkness and, in particular, red light protect the eye against DFX toxicity. This is of potential use in patient management during DFX therapy.

Animals↗

Control of oxidative damage in rheumatoid arthritis by gold(I)-thiolate drugs.

The roles of anti-arthritic gold(I)-thiolate drugs such as disodium aurothiomalate ('Myocrisin') in the modulation or promotion of oxygen radical-mediated oxidative damage in vivo are reviewed. In particular, the precise molecular mechanisms by which these novel second-line agents exert their therapeutic effects are discussed in terms of (i) the direct and indirect control of enzymes involved in the generation or scavenging of reactive oxygen species (ROS) such as superoxide ion, hydrogen peroxide and hydroxyl radical, (ii) the protection of proteins and relevant enzyme systems against attack by ROS and (iii) their direct involvement in the production (at appropriate 'target' sites) or scavenging of ROS in vivo. In addition, the role of the orally-effective gold(I)-phosphine complex auranofin in the control of oxidative damage in rheumatoid arthritis is also discussed.

Antirheumatic Agents↗

A neurogenic mechanism for symmetrical arthritis.

Human synovium is richly innervated by autonomic and sensory nerve fibres, many of which contain neuropeptides. The hypothesis is that, in addition to a sensory role, some of these fibres modulate the response of the synovial membrane to a variety of noxious stimuli by releasing these peptides. Synovial damage results in acute inflammation in the damaged joint and a neurogenically mediated infiltrate of inflammatory cells in the contralateral joint. These cells might protect the contralateral synovium from injury similar to that in the damaged joint. An increased response would lead to synovitis and symmetrical disease.

Arthritis↗

Effects of oxidative stress on some physiochemical properties of caeruloplasmin.

We report the effects of oxidative stress generated by low-intensity u.v. irradiation (366 and 254 nm), dialysis against ascorbate and isolated stimulated neutrophils on some physicochemical properties of caeruloplasmin. Low-intensity u.v. irradiation resulted in a loss of ferroxidase activity and 610 nm absorption, changes previously reported to occur during storage and manipulation of caeruloplasmin. These alterations were found to correspond to aggregation of the protein, induction of visible fluorescence (excitation, 360 nm; emission, 454 nm), changes in c.d. spectra which were indicative of alterations in protein conformation, loss of half-cystine, tryptophan and tyrosine content and loss immunoreactivity. The changes in the far-u.v. c.d. spectrum of caeruloplasmin were more pronounced than those observed for u.v.-irradiated IgG. Similar c.d. changes and induction of fluorescence were observed following dialysis of caeruloplasmin against ascorbate or exposure to stimulated neutrophils. It is concluded that the lability of caeruloplasmin may arise from oxidative modification, in addition to the previously described susceptibility of this protein to proteolysis.

Amino Acids↗

Hypoxic-reperfusion injury in the inflamed human joint.

A series of experiments showed that, on exercise of the inflamed human knee, intra-articular pressure rises above synovial capillary perfusion pressure, causing intra-articular hypoxia; and that, on cessation of exercise, there is oxidative damage to lipids and IgG within the joint. These findings are consistent with the hypothesis that persistence of synovial inflammation can be due to exercise-induced hypoxic-reperfusion injury mediated by reactive oxygen species.

Adult↗