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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical trials performed with bovine superoxide dismutase (SOD) are reviewed. SOD, applied intraarticularly at a dosage of 2-16 mg, proved to be effective in osteoarthritis of the knee joint in three placebo-controlled and one steroid-controlled double-blind trials. Its efficacy in other inflammatory joint disorders is documented by uncontrolled trials. Similarly, some controlled and many open studies support the efficacy of locally injected SOD in periarticular inflammation. Systemic treatment of rheumatoid arthritis by SOD at the dosages indicated yielded disappointing results. Well documented, though open uncontrolled studies demonstrated beneficial effects of locally administered SOD in radiation cystitis, interstitial cystitis and Peyronie's disease. Tolerance is good, but allergic reactions at low incidence have to be anticipated. Human SOD derived from recombinant microorganisms is being developed to explore its therapeutic potential particularly in ischemia-reperfusion damage, adult respiratory distress or similar conditions.
Mol Cell Biochem 1988 Dec
PMID:Superoxide dismutase for therapeutic use: clinical experience, dead ends and hopes. 306 19

Morphometric analysis of endothelium in rabbit lungs demonstrated a dramatic effect of platelet-activating factor (PAF) on the ultrastructure of pulmonary vasculature. Plasmalemmal vesicles in capillaries were increased both in size (638 A PAF vs 538 A control) and in number (386/micrograms 3 cytoplasm PAF vs 125/micrograms 3 cytoplasm control) when PAF was administered as a single acute low dose (chi less than 3 micrograms/kg). High concentrations of PAF (chi greater than 3 micrograms/kg) as a single acute dose also increased vesicle number (203/micrograms 3 cytoplasm), but frequently precipitated the respiratory distress syndrome. Chronic administration of PAF with daily doses over periods of either 3.5 or 7 weeks resulted in changes paralleling the acute observations, but did not lead to more extensive lung disease.
Exp Mol Pathol 1983 Feb
PMID:Platelet-activating factor effects on pulmonary ultrastructure in rabbits. 683 35

Intra-alveolar fibrin deposition is a cardinal feature of neonatal respiratory distress syndrome and likely contributes to short-term and long-term morbidity. Previous studies have shown that fetal distal lung epithelial cell (FDLE) surfaces express procoagulant activity when incubated with adult plasma and may therefore provide one mechanism by which fibrin is generated. However, plasma concentrations of prothrombin and thrombin inhibitors differ significantly at birth and during the first weeks of life compared with adult values. Therefore, we measured thrombin-generating capacity and inhibitor complex formation in cord and adult plasma incubated in the presence of FDLE. Although starting cord plasma concentrations of prothrombin were 43% of adult values, the amount of thrombin generated was decreased by only 21%. When cord plasma concentrations of prothrombin were selectively increased to adult values, the amount of thrombin generated surpassed adult plasma by 89%. The latter observations suggested that thrombin inhibition was impaired in cord plasma compared with adult plasma and supplementation of cord plasma with antithrombin III (ATIII) as well as prothrombin returned thrombin generation to adult levels. However, the percentage of thrombin complexed to inhibitors (59%) at the completion of the experiments was similar in cord, cord plus prothrombin, cord plus prothrombin plus ATIII, and adult plasmas. Although a higher proportion of thrombin was inhibited by alpha 2-macroglobulin (alpha 2M) in cord plasma and cord plasma plus prothrombin, this did not compensate for the decreased amount of thrombin inhibited by ATIII. When cord plasma was supplemented with ATIII as well as prothrombin, the proportions of thrombin complexed by the different inhibitors were similar to those of adult plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Jul
PMID:Thrombin inhibition by fetal distal lung epithelium is different in fetal and adult plasma. 751 42

Platelet-activating factor (PAF) is a proinflammatory mediator known to elicit changes in airway reactivity and vascular permeability, and it may also have a role in the development and progression of acute respiratory distress syndrome and asthma. We have developed a mouse model to test the hypothesis that these traits were controlled by a single gene and were mechanistically related. We further hypothesized that there was a relationship between PAF-induced hyperreactivity and baseline reactivity to acetylcholine (ACh). Among eight inbred strains of mice that exhibited significant interstrain variation in ACh reactivity, intravenous PAF induced 16 to 278% increases in reactivity to ACh (25 micrograms/kg). PAF also elicited 95 to 307% increases in lung permeability as measured by Evans blue extravasation. Both reactivity and permeability changes induced by PAF were blocked by a PAF receptor antagonist (L-659,989). Strain distribution patterns for baseline reactivity to ACh and PAF-induced hyperreactivity and lung permeability were not significantly concordant, and suggest that the variables were not interdependent. Progeny derived from AKR/J (PAF hyperresponsive) and C3H/HeJ (PAF hyporesponsive) mice were characterized for their PAF responsiveness as determined by PAF-induced hyperreactivity and hyperpermeability. The ratios of hyperresponsive and hyporesponsive phenotypes in outcross progeny were compared to those predicted for Mendelian inheritance and assessed for relatedness by chi 2 and cosegregation analyses. Results suggested that PAF-induced hyperreactivity was controlled by a single gene, but PAF-induced hyperpermeability was controlled by a more complicated interaction of factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Nov
PMID:Susceptibility to platelet-activating factor-induced airway hyperreactivity and hyperpermeability: interstrain variation and genetic control. 757 95

Specific changes in composition and content of lung extracellular matrix (ECM) proteoglycans (PGs) and hyaluronan (HA) have been observed during the acute response to damage in several forms of injury including infant respiratory distress syndrome (IRDS). These ECM components are thought to modulate the healing response. Hyperoxia, a contributing factor to IRDS, is known to damage both adult and developing lung, however, the extent and pattern of impairment depends on lung maturity. We hypothesized that exposing neonatal rats to hyperoxia alone might result in changes in lung HA, as well as in age-specific changes in lung PGs, similar to those shown to occur in IRDS. In control rats, lung HA decreased over the first 10 days of life, whereas rats exposed to hyperoxia exhibited a time-dependent, time-limited increase in both lung HA and lung wet weight. Histochemistry showed the HA in hyperoxia-exposed lungs to be accumulated in perivascular cuffs of medium sized arteries, and in the alveolar walls. Rats were then exposed to normoxia or hyperoxia for 7 days beginning at either 3 days of life (neonatal) or 21 days (adolescent), and lung tissue was cultured in the presence of [35S]-sulfate to label newly synthesized PGs. Proteoglycans were extracted, and analyzed by isopycnic CsCl gradient centrifugation, sequential enzymatic deglycosylation, size chromatography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). When controlled for total protein extracted, 63% more label was incorporated into large molecular weight material in the tissue exposed to hyperoxia, with a 95% increase in incorporation in the most dense fraction, D1. [35S]-Sulfate incorporation into chondroitin and dermatan sulfate in hyperoxic tissue specifically increased 116% (242% in the D1 fraction), while incorporation into heparan sulfate remained essentially unchanged. There was a nearly fivefold increase in [35S]-sulfate incorporation into chondroitin sulfate chains in the D1 fraction. When the D1 fractions of extracts of treated and control rat lungs were compared on SDS-PAGE, a large chondroitin sulfate proteoglycan (CSPG; core protein of 195 kDa) was upregulated in the D1 fraction from hyperoxic tissue of neonatal rats, but was not detected in the lungs of adolescent animals exposed to hyperoxia. This CSPG and four additional large CSPGs were noted to be upregulated on western blotting by a polyclonal antibody directed against the G1 domain of the aggrecan protein core. We conclude that hyperoxia alone causes an increase in lung HA and lung water, and speculate that this contributes significantly to the clinical syndrome of IRDS. In addition, several large CSPGs are upregulated by hyperoxic exposure in a developmentally specific manner. We speculate that this increase in CSPGs may interfere with the normal developmental sequence of events, contributing to hypoalveolarization.
Am J Respir Cell Mol Biol 1995 Dec
PMID:Hyperoxia alone causes changes in lung proteoglycans and hyaluronan in neonatal rat pups. 757

Little is known of the pathophysiology of invasive pulmonary aspergillosis (IPA), an opportunistic fungal infection usually caused by Aspergillus fumigatus. It has been suggested that the ability of the fungus to degrade elastin may aid its invasion and growth in lung tissue. We have described previously the construction of a strain of A. fumigatus in which the gene encoding an alkaline protease, AFAlp, had been disrupted (C.M. Tang, J. Cohen, and D.W. Holden, Mol. Microbiol. 6:1663-1671, 1992); this mutant is deficient in extracellular proteolytic and elastinolytic activity over a broad pH range. In this study, we compared the pathogenicity of this and another AFAlp disruptant with their isogenic, elastase-producing parental strains in two murine models of IPA. In both models, animals were inoculated via the respiratory tract. In the first model, the inoculum was delivered as airborne conidia and animals developed signs of respiratory distress within 2 to 4 days. In the second model, conidia were administered intranasally as a suspension and the disease developed over a 2-week period. No difference was observed between the wild-type and AFAlp disruptants in terms of mortality, and elastin breakdown was detected in lung tissue from animals inoculated with all four strains. We conclude that AFAlp is not a virulence determinant in these models of IPA.
 ...
PMID:The alkaline protease of Aspergillus fumigatus is not a virulence determinant in two murine models of invasive pulmonary aspergillosis. 847 53

To understand the basis for the refractory nature of acute respiratory distress syndrome (ARDS) to glucocorticoids, the effects of dexamethasone pretreatment (DEX, 2 mg/kg, intraperitoneally) on the kinetics of airway tumor necrosis factor-alpha (TNF alpha) and macrophage inflammatory protein 2 (MIP-2) production, and polymorphonuclear leukocyte (PMN) influx after intratracheal lipopolysaccharide (LPS) (1 mg/kg) in rats were investigated. In the absence of exogenous glucocorticoids, TNF alpha and MIP-2 levels in bronchoalveolar lavage (BAL) fluid peaked at 21 and 300 ng, respectively, by 3 h. DEX pretreatment resulted in a 74% reduction in BAL TNF alpha, yet MIP-2 accumulation was unchanged. In addition, DEX reduced PMN influx at 5 h by 58.4% to 4.1 +/- 0.7 x 10(6) PMN (n = 5). DEX, however, did not mitigate the 3-fold increase in total BAL protein observed at 5 h, attributable to albumin influx. The effects of subacute DEX treatment (3.8 mg/kg per day, for 3 days) on cell-surface expression of the adhesion molecules CD11a, CD11b, and L-selectin were determined by flow cytometric analysis of peripheral blood and autologous BAL PMN. Compared with peripheral blood PMN, exudative PMN had 4-fold greater CD11b expression, no change in CD11a, and loss of L-selectin immunoreactivity 5 h after LPS challenge. The upregulation of CD11b on exudative PMN was insensitive to DEX pretreatment, which, together with a failure to suppress MIP-2 levels, provides a possible explanation for the lack of efficacy of steroids in the management of ARDS.
Am J Respir Cell Mol Biol 1996 Jul
PMID:Glucocorticoid effects in an endotoxin-induced rat pulmonary inflammation model: differential effects on neutrophil influx, integrin expression, and inflammatory mediators. 867 28

Genetic ablation of the murine SP-B gene in transgenic mice caused lethal perinatal respiratory distress in homozygous offspring, whereas heterozygous SP-B (+/-) mice survived postnatally. In adult SP-B(+/-) mice, surfactant protein B mRNA and the alveolar lavage SP-B protein were reduced by 50% compared with wild-type littermates, consistent with the inactivation of a single SP-B allele. Expression of SP-A, SP-C, and SP-D proteins was not affected in SP-B(+/-) mice. Heterozygous SP-B(+/-) mice reached maturity in numbers expected by Mendelian inheritance of a recessive gene. Lung morphology and both intracellular and extracellular phospholipid pool size and composition were unaltered in the SP-B(+/-) mice. Despite normal survival, pulmonary function studies demonstrated a consistent decrease in lung compliance in SP-B(+/-) mice. Abnormalities of inflation/deflation curves demonstrated airway collapse at low deflation pressures. Residual volumes were increased in the SP-B(+/-) mice. In summary, SP-B mRNA and SP-B protein were reduced by 50% in SP-B(+/-) mice, resulting in abnormalities of lung compliance and air trapping, suggesting a potential susceptibility to pulmonary dysfunction associated with SP-B deficiency.
Am J Respir Cell Mol Biol 1997 Jan
PMID:Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice. 899 78

Familial infantile myasthenia is an autosomal recessive disorder, recently classified as congenital myasthenic syndrome type Ia. Onset of symptoms is at birth to early childhood with significant myasthenic weakness and possible respiratory distress, followed later in life by symptoms of mild to moderate myasthenia. Thirty-six patients of 12 families, seven of them consanguineous, were used to map the familial infantile myasthenia gene. A combination of linkage search through the genome, DNA pooling and homozygosity mapping were employed resulting in the localisation of this disease locus to the telomeric region of chromosome 17p. A maximum lod score of 9.28 at theta = 0.034 was obtained between the disease locus and marker locus D17S1537. Haplotype analysis showed all families to be consistent with linkage to this region thus providing evidence for genetic homogeneity of familial infantile myasthenia. Multipoint linkage analysis mapped the disease gene in the approximately 4.0 cM interval between marker loci D17S1537 and D17S1298 with a maximum multipoint lod score of 12.07. Haplotype analysis and homozygosity by descent in affected individuals of the consanguineous families revealed results in agreement with the confinement of the familial infantile myasthenia region within the interval between marker loci D17S1537 and D17S1298.
Hum Mol Genet 1997 Apr
PMID:Mapping of the familial infantile myasthenia (congenital myasthenic syndrome type Ia) gene to chromosome 17p with evidence of genetic homogeneity. 909 70

Lung injury in the acute respiratory distress syndrome (ARDS) is in part due to polymorphonuclear leukocyte (PMN)-mediated oxidative tissue damage. By means of nuclear factor-kappaB (NF-kappaB) activation, oxidants may also induce several genes implicated in the inflammatory response. The dithiocarbamates are antioxidants with potent inhibitory effects on NF-kappaB. We postulated that the pyrrolidine derivative pyrrolidine dithiocarbamate (PDTC) would attenuate lung injury following intratracheal challenge with endotoxin (lipopolysaccharide; LPS) through its effect as an antioxidant and inhibitor of gene activation. Rats were given PDTC (1 mmole/kg) by intraperitoneal injection, followed by intratracheal administration of LPS. The transpulmonary flux of [125I] albumin (permeability index; PI) was used as a measure of lung injury. Northern blot analysis of total lung RNA was performed to assess induction of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) as markers of NF-kappaB activation. The effect of in vivo treatment with PDTC on LPS-induced NF-kappaB DNA binding activity in macrophage nuclear extracts was evaluated with the electrophoretic mobility shift assay (EMSA). PDTC administration attenuated LPS-induced increases in lung permeability (PI = 0.16 +/- 0.02 for LPS versus 0.06 +/- 0.01 for LPS + PDTC; P < 0.05). TNF-alpha levels and PMN counts in bronchoalveolar lavage fluid (BALF) were unaffected, as were whole-lung TNF-alpha and ICAM-1 mRNA expression. PDTC had no effect on NF-kappaB activation as evaluated with EMSA. PDTC reduced lung lipid peroxidation as assessed by levels of malondialdehyde, without reducing neutrophil oxidant production. We conclude that PDTC attenuates LPS-induced acute lung injury. This effect occurs independently of any effect on NF-kappaB. PDTC reduces oxidant-mediated cellular injury, as demonstrated by a reduction in the accumulation of malondialdehyde. Administration of PDTC may represent a novel approach to limiting neutrophil-mediated oxidant injury.
Am J Respir Cell Mol Biol 1997 Nov
PMID:Pyrrolidine dithiocarbamate attenuates endotoxin-induced acute lung injury. 937 12


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