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At least 37 records · Page 2Linked to original sources
PubMed2026

TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

anterior segment dysgenesis↗
PubMed2026

Congenital Laryngomalacia: Pathophysiology, Clinical Spectrum, and Holistic Management.

Congenital laryngomalacia is the most common cause of infant stridor and arises from interacting structural, neuromuscular, and inflammatory mechanisms that produce dynamic supraglottic collapse. Disease severity spans mild stridor to significant obstruction, aspiration, and failure to thrive, often influenced by comorbid medical conditions. Diagnosis relies on flexible laryngoscopy supported by instrumental swallowing studies and microdirect laryngoscopy and bronchoscopy when indicated. Most infants respond to conservative management, particularly targeted feeding modifications, while acid suppression offers benefit in selective cases. Supraglottoplasty provides effective, durable improvement for severe disease and significantly enhances infant outcomes and family quality of life.

Humans↗
PubMed1979

A tissue-culture model of cartilage breakdown in rheumatoid arthritis. Quantitative aspects of proteoglycan release.

1. The destruction of articular cartilage in human rheumatoid and other arthritides is the result of diverse mechanical, inflammatory and local cellular factors. A tissue-culture model for studying cartilage-synovial interactions that may be involved in the final common pathway of joint destruction is described. 2. Matrix breakdown was studied in vitro by using bovine nasal-cartilage discs cultivated in contact with synovium. Synovia were obtained from human and animal sources. Human tissue came from patients with ;classical' rheumatoid arthritis, and animal tissue from rabbits with antigen-induced arthritis. 3. Cartilage discs increased their proteoglycan content 2-3-fold during 8 days in culture. Proteoglycan was also released into culture medium, approx. 70% arising from cartilage breakdown. 4. Synovial explants from human rheumatoid and rabbit antigen-induced arthritis produced equivalent stimulation of proteoglycan release. After an initial lag phase, the breakdown rate rose abruptly to a maximum, resulting in a 2-fold increase of proteoglycan accumulation in culture medium after 8-10 days. 5. High-molecular-weight products shed into culture media were characterized chromatographically and by differential enzymic digestion. Proteoglycan-chondroitin sulphate accounted for 90% of the released polyanion, and its partial degradation in the presence of synovial explants was consistent with limited proteolytic cleavage. 6. Rheumatoid synovium applied to dead cartilage increased the basal rate of proteoglycan release. Living cartilage was capable of more extensive autolysis, even in the absence of synovium. However, optimal proteoglycan release required the interaction of living synovium with live cartilage. These findings support the view that a significant component of cartilage breakdown may be chondrocyte-mediated.

Animals↗
PubMed1979

Effect of hypersensitivity on protein uptake across the air-blood barrier of isolated rabbit lungs.

In previous studies with isolated perfused rabbit lungs, we observed that human serum albumin (HSA) and ovalbumin, introduced into the isolated lungs as an aerosol, entered the pulmonary circulation antigenically intact. The "inhaled" proteins were also broken down in the lung. When lungs from animals immunized with one protein inhaled the two proteins simultaneously, absorption of intact antigen was specifically reduced, and there was a nonspecific increase in the appearance of metabolites of both proteins in the blood. In the present study, we investigated the antigen-specific and nonspecific effects of two types of hypersensitivity responses on protein absorption across the air-blood barrier of isolated rabbit lungs. In one group of lungs, an acute hypersensitivity response was induced by introducing HSA into the blood perfusing lungs from HSA-immunized rabbits. In another, the rabbits had been previously exposed to chronic HSA aerosol until their lungs exhibited a chronic immunologic inflammatory response. Lungs from both groups were insufflated simultaneously with HSA, and a nonspecific protein, ovalbumin. Lungs in which the acute anaphylactic response was induced showed no alteration in the absorption of either intact protein compared with HSA-immunized controls, but absorbed a somewhat larger quantity of breakdown products of the specific antigen. Lungs undergoing the chronic alveolar inflammation were more permeable to nonspecific protein than were noninflamed lungs. Despite the increased permeability to nonspecific protein, the absorption of antigen was blocked as effectively as in immune but noninflamed controls. In these chronically inflamed lungs, the absorption of antigen breakdown products was enhanced. The results indicate that both immunologic and inflammatory mechanisms may control the amounts of inhaled soluble proteins that reach the blood via the alveolocapillary barrier. Alterations in the absorption of inhaled proteins and their metabolites across the air-blood barrier during certain types of hypersensitivity responses may be of immunologic and pathologic significance.

Absorption↗
PubMed2026

Myeloid Dendritic Cell Counts and Coronary Heart Disease: a Bidirectional Mendelian Randomization Study.

BACKGROUND: Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide, with immune and inflammatory mechanisms playing important roles in its pathogenesis. Dendritic cells (DCs) are key regulators of immune responses; however, the relationship between specific DC subsets and CHD risk remains incompletely understood. METHODS: This study conducted a bidirectional two-sample Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) summary statistics to investigate the potential associations between circulating dendritic cell traits and CHD. Genetic instruments for myeloid dendritic cells (Myeloid DCs) and plasmacytoid dendritic cells (Plasmacytoid DCs), including both absolute counts and relative proportions, were obtained from immune cell GWAS datasets. Summary statistics for CHD were derived from a large European-ancestry population. Multiple MR methods were applied, and sensitivity analyses were performed to assess the robustness of the findings and potential pleiotropic effects. RESULTS: Nominal associations between genetically predicted Myeloid DC counts and CHD risk were observed in the MR-Egger and weighted median analyses, whereas the inverse variance weighted analysis demonstrated no significant association. These nominal associations did not remain statistically significant after correction for multiple testing. No significant associations were observed for Plasmacytoid DC counts or for the relative proportions of either DC subset. Reverse MR analyses were inconclusive due to wide confidence intervals, precluding meaningful inference regarding a causal effect of CHD on DC-related traits. Sensitivity analyses revealed no substantial heterogeneity or horizontal pleiotropy. CONCLUSIONS: This bidirectional MR study explored the potential relationships between circulating dendritic cell traits and CHD risk. Although nominal associations involving Myeloid DC counts were observed in secondary MR analyses, no robust evidence supporting an association remained after correction for multiple testing. Further studies using larger datasets and functional approaches are warranted to clarify the role of dendritic cells in CHD.

Humans↗
PubMed1979

[Multiple recurrent paralysis of the cranial nerves (author's transl)].

The authors describe three patients presenting several episodes of paralysis of the motor and sensory cranial nerves and discuss possible aetiological factors. The paralytic attacks were regressive and were repeated at irregular intervals over a period of several years. It was confirmed that no local or general cause for the symptoms existed and the conclusion was reached that they were part of an autonomous clinical syndrome of unknown aetiology. Other cases have been reported in the published literature in which a non-specific inflammatory mechanism is suggested but no biological or pathological basis exists to support this physiopathological hypothesis. The clinical syndrome follows a benign course, the paralysis being regressive and the affection remaining confined to the peripheral nervous system of mesencephalic origin.

Aged↗
PubMed1978

Mucha-Habermann's disease in children: treatment with erythromycin.

Safe therapeutic measures for Mucha-Habermann's disease in children are lacking. Three patients with the disease were treated with erythromycin for systemic effect. Although the series is small and uncontrolled, this approach seemed effective. An anti-inflammatory mechanism related to inhibition of chemotaxis is speculated.

Child↗
PubMedDate not supplied

Rheumatoid arthritis: an immune disease in search of an etiology.

The current knowledge of the immunologic and etiologic factors which play a role in rheumatoid arthritis is reviewed and extrapolated to the systemic effects of rheumatoid disease. The disease process is viewed as the incidental result of an atypical immuno-inflammatory mechanism initiated by an unidentified antigenic stimulus.

Anemia↗
PubMed1977

Acute pseudogout in the absence of synovial fluid Leukocytes.

A case of acute pseudogout that occurred in the absence of synovial fluid leukocytes is described. This finding implies that there may be an alternative inflammatory mechanism for acute pseudogout that does not depend on polymorphonuclear leukocytes.

Acute Disease↗
PubMed1976

The biochemical prerequisites for preventing pathogenic lysolecithin activity in the human gallbladder.

Human gallbladder epithelium was disintegrated to complete loss of microscopic structure and incubated at 37 degree C together with unlabelled lysolecithin and 14C-lysolecithin. During each incubation lysolecithin was degraded and stoichiometrically equivalent amounts of free fatty acids formed. The maximum rate of degradation was obtained at pH 7.0 and at 200 muM lysolecithin. With increasing amounts of gallbladder epithelial cell constituents the reaction became faster. After heating the epithelial components at 70 degrees C for 10 min the reaction was inhibited. The results suggest the presence of a heat labile lysophospholipase (phospholipase B) activity in the human gallbladder epithelium. This activity may operate to protect the gallbladder epithelium against potentially pathogenic lysolecithin activity. Its presence in the gallbladder epithelium meets the prerequisites for a local anti-inflammatory mechanism and lends further support to the hypothesis of lysolecithin as a mediator of cholecystitis.

Cholecystitis↗
PubMed1977

Mechanism for the inflammatory response in primate lungs. Demonstration and partial characterization of an alveolar macrophage-derived chemotactic factor with preferential activity for polymorphonuclear leukocytes.

Approximately 4 h after an initial bronchoalveolar lavage (BAL) of a primate's lung, an appreciable number of polymorphonuclear leukocytes (PMNs) were noted to accumulate in respiratory fluids when lavage was repeated. Whereas, alveolar macrophages (90%) and lymphocytes (7%) were the principal respiratory cells recovered initially from lavage fluid, later samples contained 45-90% PMNs To explain the observed ingress of PMNs into lung fluids, concentrated BAL fluid was tested for chemoattractant activity. Such fluid obtained 4 and 24 h after an initial lavage contained material that produced directed migration (chemotaxis) for PMNs and mononuclear cells isolated from peripheral blood of normal donors. Gel filtration chromatography of BAL disclosed two peaks of chemotactic activity in the effluent fractions. Material from the column with an estimated molecular weight of 15,000 daltons was chemotactic for both PMNs and mononuclear cells. Because it was susceptible to inactivation with antiserum against the fifth component of complement, resistant to heating, and unaffected by antiserum against C3, this factor was considered analogous to the cleavage product of the fifth component of complement. C5a. In addition chemotactic activity for PMNs only was contained in an effluent peak having a molecular weight of about 5,000 daltons. This material was heat labile but unaffected by antisera to complement components. To locate the possible source of these factors in respiratory fluid, in vitro cultures of alveolar macrophages were established. These cells, whether stimulated by phagocytosis of opsonized bacteria or merely by attachment to a glass surface, produced chemotactic material which had physical characteristics similar to the small molecular weight material in BAL. Moreover, it induced preferential chemotaxis for PMNs. Thus, in primate lungs, at least two chemotactic substances may generate an inflammatory response; one which is a fragment of the complement component C5 and another small molecular weight factor which is released from alveolar macrophages.

Animals↗
PubMed1976

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone greater than spironolactone greater than phenylbutazone (PBZ) greater than aspirin (ASA) greater than indomethacin (IDM). Concentration ratios required to obtain significant displacement of [3H]aldosterone were high but clearly within the therapeutic range for PBZ and ASA but not IDM. The analogues oxyphenbutazone (OBZ) and sodium salicylate (SS) were similar in binding activity to PBZ and ASA, respectively. Lineweaver-Burk analysis revealed that the inhibition of [3H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of [3H]aldosterone. In vivo injection of PBZ and ASA resulted in competition for [3H]aldosterone renal binding comparable to the in vitro studies. Administration of PBZ and OBZ to adrenalectomized rats resulted in significant salt retention whereas ASA and SS did not differ significantly from controls. Salt retention elicited by PBZ and OBZ was inhibited by spironolactone, a competitive mineralocorticoid antagonist. These data suggest that, despite nonsteroidal structures, PBZ and OBZ induce salt retention via a receptor-mediated mineralocorticoid pathway analogous to aldosterone action.

Aldosterone↗
PubMed1976

Inflammatory cells in solid murine neoplasms. I. Tumor disaggregation and identification of constituent inflammatory cells.

Mechanical and enzymatic methods of disaggregating tumors were studied with the goals of (1) minimizing cell losses while (2) maintaining functional and surface membrane markers needed to objectively identify inflammatory cells (IC)1 in resultant suspensions. Application of the principles and methods described makes accurate estimation of the percentage of each IC type present in neoplasms possible for the first time. Compared to purely mechanical means of disaggregating tumors, all enzyme mixtures tested markedly increased yields of viable cells/g neoplasm. Best results were obtained with a combination of collagenase and a protease of broader substrate range (alpha chymotrypsin, papain, pronase or trypsin). The combination of enzymes that gave the highest yields with the least effect on inflammatory cell markers was trypsin, collagenase and DNAse (TCD). Because mechanical injury appeared to be the greatest single cause of cell loss (the enzymes themselves had little direct effect), potential sources were identified and either eliminated or minimized. With TCD, depending on the tumor system, cell recovery (measured as DNA recovered in cell suspensions) was as high as 50% and yields were as much as 6.9 X 10(8) viable cells/g tumor. Complete disaggregation was not required to obtain representative IC populations from tumor fragments. Neutrophils, eosinophils and mast cells from disaggregated neoplasms were counted in Giemsa stained cytocentrifuge preparations based on their unique morphologic appearances. Macrophages were identified by their capacity to phagocytose zymosan, a function which proved highly resistant to the effect of enzymes. Flourescent microscopic identification of brain associated thymus antigen (BATA) allowed quantification of T lymphocytes, since this marker was virtually unchanged by enzyme exposure. Surface immunoglobulin (Ig) was stripped from B lymphocytes most rapidly by pronase and chymotrypsin, slowly by trypsin and papain, and not at all by collagenase. Ig positive cells therefore could be quantified in suspensions generated by collagenase or very short (20 min) exposure of fragments to trypsin.

Animals↗
PubMed1977

Mechanism of anti-inflammatory action of glucocorticosteroids.

Glucocorticosteroids react with blood monocytes and tissue macrophages to produce a peptide factor which stimulates the random migration of polymorphs in vitro in the capillary-tube migration system. An identical effect on polymorph migration is produced by colchicine and vinblastine, drugs which inhibit the assembly of the cytoplasmic microtubules on which the functional activity of polymorphs depends. Pharmacological agents which inhibit microtubular assembly indirectly by increasing intracellular cyclic adenosine monophosphate (A.M.P.), also stimulate polymorph migration in vitro. These observations suggest that the anti-inflammatory activity of glucocorticosteroid drugs is mediated by a peptide hormone which inhibits polymorph microtubular assembly. Many peptide hormones are believed to act by increasing the concentration of cyclic A.M.P. within target cells and this mechanism is probably also responsible for the inhibitory effect of steroids on phagocytic cells.

Adenylyl Cyclases↗
PubMed1978

On the mechanism of the anti-inflammatory action of the newly-synthesized benzoylpyrazolone derivatives.

One of the basic mechanisms of action of the nonsteroid anti-inflammatory agents is associated with prostaglandin synthesis. The effects of 1-phenyl-3-methyl-4 (4)-chlorbenzoylpyrazolone-5 (No. 151) and 1-phenyl-2-benzoyl-3-methylpyrazolone-5 (No. 76) on the quantity of prostaglandins and on the invasion of polymorphonuclear leucocytes in inflammatory exudate have been studied. Experimental inflammation is induced after Higgs et al. (1976). The level of prostaglandins in the exudate is determined through cascade superfusion of isolated smooth-muscle organs. The level of prostaglandins is found to decrease in animals treated with No. 151 and indomethacine, and to increase under the effect of No. 76. The invasion of the focus with polymorphonuclear leucocytes is inhibited by No. 151 and indomethacine. On the basis of the results obtained, No. 151 is assumed to belong to the group of prostaglandin-synthetase inhibitors, according to its mechanism of action.

Animals↗
PubMed1976

Pharmacologic modulation of inflammatory mediator release by rat mast cells.

Current knowledge of the mechanism of inflammatory mediator release from mast cells is reviewed with particular reference to the role of cyclic nucleotides and calcium and their interrelationship with one another as defined by studies in highly purified rat peritoneal mast cells. Data are presented indicating an important role for intracellular cAMP and calcium in the mediation or modulation of release, as well as evidence for a close relationship between these two regulatory systems. Releasing agents which clearly act at the level of the plasma membrane (concanavalin A and anti-IgE antibody) are shown to differ from releasing agents that may not (48/80 and the ionophore A23187) in regard to the early cellular cAMP response, dependency of the release reaction on phosphatidyl serine, and kinetics of release. Pharmacologic modulators of release are discussed; these include: PGE1 and theophylline, which raise cAMP and inhibit release; and diazoxide, adenine, and carbachol which lower cAMP and potentiate release. Adenosine was also found to enhance release with marked effects at concentrations in the low nanomolar range.

Animals↗
PubMed1979

Fate of herpes simplex virus in lymphocytes from inflammatory joint effusions. ii. Mechanisms of non-permissiveness.

Mononuclear cells which were isolated from rheumatoid synovial effusions and cultured without prior separation failed to support the growth of herpes simplex virus (HSV). However, subpopulations of T lymphocytes separated on the basis of cell size or receptors for sheep red cells were, in isolation, permissive for this virus. Virus growth in these permissive cells was blocked by cocultivation with the remaining mononuclear cell populations.

Arthritis, Rheumatoid↗