Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silica is a well-known occupational fibrogenic agent and its primary target cell is alveolar macrophage. Particle-stimulated macrophages are believed to release various mediator which can regulate the inflammation as well as pulmonary fibrosis. Even though oxygen radicals play the major role among these mediators, the mechanisms concerning the stimulation of alveolar macrophages are not clear yet. The present study was carried out to investigate the signal transduction pathway on oxygen radical generation in silica-stimulated alveolar macrophages. Silica induced oxygen radical generation in a dose-response pattern. Extracellular calcium depletion, calcium channel blockers, and calcium release blocker decreased the effect of silica on oxygen radical generation. Silica increased intracellular calcium through the influx of calcium through the calcium channel and the calcium release from the intracellular calcium store. To know the role of protein kinase C (PKC), phospholipase C (PLC), and protein tyrosine kinase (PTK) in silica-induced oxygen radical generation, we pretreated alveolar macrophages with inhibitors of these enzymes. Inhibitors of PKC (sphingosine and staurosporine), PLC (neomycin and U-73122), and PTK (genistein and erbstatin) suppressed the silica-induced oxygen radical generation. Silica increased the PLC activity at the concentration of 5 mg/ml. The inhibitors of PTK and PLC suppressed the action of silica on the PLC activity. From these results, we suggest that silica induces oxygen radical generation through PTK, PLC, and PKC in alveolar macrophages.
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PMID:Silica-induced oxygen radical generation in alveolar macrophage. 924 22

Pulmonary arterial hypertension is common in patients with SSc. Fig. 1 shows the diagnostic and therapeutic approach to PAH in SSc. Doppler echocardiography may suggest the diagnosis, but RHC is necessary to confirm PAH and to measure vasoreactivity. Therapy is directed at the underlying connective tissue disease. Vasoreactive patients often benefit from therapy with high-dose calcium-channel [figure: see text] blockers, but most patients are not vasoreactive. Intravenous epoprostenol and oral endothelin-1 receptor antagonists improve hemodynamic measurements and symptoms in SSc-associated PAH. The therapy of right ventricular failure is focused on vasodilators, inotropes, and diuretics with careful attention to avoiding systemic hypotension. The scleroderma pulmonary-renal syndrome and the scleroderma renal crisis are distinct syndromes with different clinical presentations, histopathologic manifestations, treatments, and outcomes. The scleroderma pulmonary renal syndrome is an autoimmune vasculitis of kidney and lung associated with normal blood pressure. Treatment is supportive, and prognosis is dismal. In contrast, scleroderma renal crisis is associated with systemic hypertension, onion skinning of afferent arterioles, and response to ACE inhibition and renal replacement therapy. Pericardial effusions are common but only occasionally lead to tamponade. Esophageal dysmotility is often associated with aspiration, leading to pulmonary fibrosis, pneumonia, or ARDS. Diffuse bowel involvement may result in pseudo-obstruction, bacterial overgrowth, or malabsorption. Prokinetic agents, antibiotics, and parenteral nutrition may be required.
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PMID:Life-threatening complications of systemic sclerosis. 1241 43

Systemic sclerosis is a multisystem disorder characterized by the presence of connective tissue sclerosis, vascular abnormalities concerning small-sized arteries and the microcirculation, and autoimmune changes. This disease is usually preceded by Raynaud's phenomenon. Cutaneous changes are useful for diagnosis. Sclerosis is initially proeminent on hands with frequently pitted scars. Telangiectases and calcium deposits are mainly observed in a good prognosis subset of the disease (CREST) characterized by the association of limited skin involvement and anti-centromere antibodies with possible late onset of pulmonary hypertension. The bad prognosis subset is associated with diffuse cutaneous sclerosis, pulmonary fibrosis, gastrointestinal disease, myocardial involvement and anti-topo-isomerase I antibodies. Histological skin changes are similar to those observed in morphea. In morphea, there is only localized sclerosis of the skin with highly variable aesthetic disability. The condition may be subdivided clinically into the following types: circumscribed plaques, linear morphea and frontoparietal lesions. The last two forms may be associated with atrophy of the underlying anatomic structures. Many other diseases may have a scleroderma-like appearance. In these diseases, nail folds abnormalities, visceral involvement and immunological changes are usually different from those observed in systemic scleroderma.
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PMID:[How to recognize scleroderma]. 1253 64

Pulmonary arterial hypertension occurs in up to 15% of patients who have systemic sclerosis (SSc) and has a high mortality. It can develop as an isolated complication or secondary to pulmonary fibrosis. There have been significant advances in assessment and therapy for this complication. Patients should be screened regularly by Doppler-echocardiography and pulmonary function tests. Right heart catheterization provides important diagnostic and prognostic information. Drawing from experience with treating primary pulmonary hypertension, treatment in the context of SSc is now possible. Patients should receive oral anticoagulation and oxygen supplementation. Calcium channel blockers are rarely effective, but parenteral prostacyclin analogs improve functional capacity and pulmonary hemodynamics. The oral endothelin-receptor blocker, bosentan, was shown to be an effective therapy for established symptomatic pulmonary hypertension in SSc. The next major challenge is to improve diagnosis and treatment of early stage or presymptomatic pulmonary hypertension with the goal of preventing this important cause of premature SSc-related mortality.
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PMID:Pulmonary hypertension in systemic sclerosis. 1284 Dec 98

Cytosolic phospholipase A2alpha (cPLA2alpha) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids. This review discusses the essential features of cPLA2alpha regulation and addresses new insights into the functional properties of this enzyme. Full activation of the enzyme requires Ca2+ binding to an N-terminal C2 domain and phosphorylation on serine residues. Ca2+ binding induces translocation of cPLA2alpha from the cytosol to the perinuclear membranes. Serine phosphorylation is mediated by mitogen-activated protein kinases (MAPKs), Ca2+/calmodulin-dependent protein kinase II, and MAPK-interacting kinase Mnk1. Interaction with proteins and lipids, which include vimentin, annexins, NADPH oxidase, phosphatidylcholine, phosphatidylinositol 4,5-bisphosphate (PIP2), and ceramide-1-phosphate, can also modulate the activity of cPLA2alpha. Recent evidence has established the physiological and pathological roles of cPLA2alpha using cPLA2alpha knockout mice. This enzyme has been implicated in fertility, striated muscle growth, renal concentration, postischemic brain injury, arthritis, inflammatory bone resorption, intestinal polyposis, pulmonary fibrosis, acute respiratory distress syndrome, and autoimmune encephalomyelitis. Now novel three paralogs, cPLA2beta, cPLA2gamma, and cPLA2delta, have been identified in humans. cPLA2gamma is distinct from others in that it is farnesylated and lacks the C2 domain. Biological roles for these new enzymes have not yet been defined.
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PMID:Regulatory mechanism and physiological role of cytosolic phospholipase A2. 1530 15

Wollastonite is a naturally occurring calcium silicate (CaSiO(3)) that is produced in both powder and fibrous forms. It is a valuable industrial mineral used in plastics, ceramics, metallurgical applications, paint, and friction products. For some applications wollastonite serves as an asbestos replacement. To varying degrees, wollastonite grades contain respirable particles/fibers, some of which have lengths and diameters that might be biologically active if deposited and retained in the lung. In this review we provide background information on wollastonite properties, markets, production and use, regulatory classification, and occupational exposure limits. We also summarize the available studies on the toxicology and epidemiology of wollastonite. We conclude that there is inadequate evidence for the carcinogenicity of wollastonite in animals and, based on strong evidence that wollastonite is not biopersistent, believe that a well-designed animal inhalation bioassay would have a negative result. The epidemiological evidence for wollastonite is limited, but does not suggest that workers are at significant risk of an increased incidence of pulmonary fibrosis, lung cancer, or mesothelioma. Morbidity studies have demonstrated a nonspecific increase in bronchitis and reduced lung function. It is prudent, however, to continue product stewardship efforts by wollastonite producers to control workplace exposures and to monitor scientific developments.
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PMID:A review of the toxicology and epidemiology of wollastonite. 1602 40

1 Bleomycin-induced lung injury is widely used as an experimental model to investigate the pathophysiology of pulmonary fibrosis but the alterations in the pharmacological responsiveness of airways isolated from bleomycin-exposed animals has been scarcely investigated. The aim of this study was to examine the in vitro tracheal responses to muscarinic receptor stimulation with carbachol in a rat bleomycin model. 2 Concentration-response curves to carbachol (10 nm to 0.1 mm) were obtained in tracheal rings isolated from Sprague-Dawley rats 14 days after endotracheal bleomycin or saline. The intracellular calcium signal in response to carbachol (10 microm) was measured by epifluorescence microscopy using fura-2 in primary cultures of tracheal smooth muscle cells from bleomycin- and saline-exposed rats. Circulating plasma tumour necrosis factor (TNF)-alpha/interleukin (IL)-1beta levels were measured by enzyme-linked immunosorbent assay. 3 Maximal contraction in response to carbachol was significantly greater in tracheal rings from bleomycin-exposed rats compared with controls (15.8 +/- 1.3 mN vs. 11.8 +/- 1.4 mN; n = 19, P < 0.05). 4 Carbachol (10 microm) elicited a transient increase of intracellular calcium with greater increment in tracheal smooth muscle cells from bleomycin-exposed rats compared with controls (372 +/- 42 nmvs. 176 +/- 20 nm; n = 7, P < 0.01). 5 Circulating plasma levels of TNF-alpha/IL-1beta were augmented in bleomycin-exposed rats compared with controls. Tissue incubation with TNF-alpha (100 ng ml(-1))/IL-1beta (10 ng ml(-1)) increased in vitro tracheal responsiveness to carbachol. 6 In conclusion, tracheal contraction in response to muscarinic receptor stimulation with carbachol was increased in bleomycin-exposed rats. This in vitro cholinergic hyperresponsiveness may be related to the augmented levels of inflammatory cytokines in bleomycin-exposed rats.
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PMID:In vitro tracheal hyperresponsiveness to muscarinic receptor stimulation by carbachol in a rat model of bleomycin-induced pulmonary fibrosis. 1687 98

The study was undertaken to investigate the influence of alpha-tocopherol on zinc, copper, iron, calcium, magnesium, and potassium concentrations in serum of rats with bleomycin-induced pulmonary fibrosis. Fourteen Wistar albino rats were randomly divided into two groups of seven animals each. The first group was treated intratracheally with bleomycin hydrochloride (BM group); the second group was also instilled with BM but received injections of alpha-tocopherol twice a week (BM+E group). The third group was treated in the same manner with saline solution only, acting as controls (C). The zinc concentrations of the BM and BM+E groups were significantly decreased compared to the controls (p<0.05). The iron concentration of the controls was significantly higher than the other two groups. The magnesium concentration in the controls and the BM+E group was significantly higher than that of the BM group. The serum copper, calcium, and potassium concentrations were not found to be statistically different among the three groups. Distinct histopathologic changes were found in the BM group compared to the untreated rats. Less severe fibrotic lesions were also observed in the BM+E group. The results of this study show that lungs of rats treated with bleomycin were seriously damaged and that vitamin E seemed to counteract some of the damage, as indicated by differences in the serum concentrations of major elements.
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PMID:Effects of alpha-tocopherol on serum trace and major elements in rats with bleomycin-induced pulmonary fibrosis. 1720

Cysteinyl leukotrienes (cysLTs) are important mediators of cell trafficking and innate immune responses, involved in the pathogenesis of inflammatory processes, i.e., atherosclerosis, pulmonary fibrosis, and bronchial asthma. The aim of this study was to examine the regulation of cysLT signaling by IFN-gamma in human primary endothelial cells. IFN-gamma increased cysLT receptor 2 (CysLTR2) mRNA expression and CysLTR2-specific calcium signaling in endothelial cells. IFN-gamma signaled through Jak/STAT1, as both AG490, a Jak2 inhibitor, and expression of a STAT1 dominant-negative construct, significantly inhibited CysLTR2 mRNA expression in response to IFN-gamma. To determine mechanisms of IFN-gamma-induced CysLTR2 expression, the human CysLTR2 gene structure was characterized. The CysLTR2 gene has a TATA-less promoter, with multiple transcription start sites. It consists of six variably spliced exons. Eight different CysLTR2 transcripts were identified in endothelial and monocytic cells. Gene reporter assay showed potent basal promoter activity of a putative CysLTR2 promoter region. However, there were no significant changes in gene reporter and mRNA t(1/2) assays in response to IFN-gamma, suggesting transcriptional control of CysLTR2 mRNA up-regulation by IFN-gamma response motifs localized outside of the cloned CysLTR2 promoter region. Stimulation of endothelial cells by cysLTs induced mRNA and protein expression of early growth response genes 1, 2, and 3 and cycloxygenase-2. This response was mediated by CysLTR2 coupled to G(q/11), activation of phospholipase C, and inositol-1,4,5-triphosphate, and was enhanced further 2- to 5-fold by IFN-gamma stimulation. Thus, IFN-gamma induces CysLTR2 expression and enhances cysLT-induced inflammatory responses.
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PMID:IFN-gamma induces cysteinyl leukotriene receptor 2 expression and enhances the responsiveness of human endothelial cells to cysteinyl leukotrienes. 1740 10

Mast cells play a significant role in the pathophysiology of many diverse diseases such as asthma and pulmonary fibrosis. Ca2+ influx is essential for mast cell degranulation and release of proinflammatory mediators, while Mg2+ plays an important role in cellular homeostasis. The channels supporting divalent cation influx in human mast cells have not been identified, but candidate channels include the transient receptor potential melastatin (TRPM) family. In this study, we have investigated TRPM7 expression and function in primary human lung mast cells (HLMCs) and in the human mast cell lines LAD2 and HMC-1, using RT-PCR, patch clamp electrophysiology, and RNA interference. Whole cell voltage-clamp recordings revealed a nonselective cation current that activated spontaneously following loss of intracellular Mg2+. The current had a nonlinear current-voltage relationship with the characteristic steep outward rectification associated with TRPM7 channels. Reducing external divalent concentration from 3 to 0.3 mM dramatically increased the size of the outward current, whereas the current was markedly inhibited by elevated intracellular Mg2+ (6 mM). Ion substitution experiments revealed cation selectivity and Ca2+ permeability. RT-PCR confirmed the presence of mRNA for TRPM7 in HLMC, LAD2, and HMC-1 cells. Adenoviral-mediated knockdown of TRPM7 in HLMC with short hairpin RNA and in HMC-1 with short interfering RNA markedly reduced TRPM7 currents and induced cell death, an effect that was not rescued by raising extracellular Mg2+. In summary, HLMC and human mast cell lines express the nonselective cation channel TRPM7 whose presence is essential for cell survival.
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PMID:Functional transient receptor potential melastatin 7 channels are critical for human mast cell survival. 1778 43


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