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)

Delayed pulmonary toxicity syndrome, characterized by interstitial pneumonia and pulmonary fibrosis, is common following high-dose bischloroethylnitrosourea (BCNU) (carmustine, [1,3-bis (2-chloroethyl)-1-nitrosourea]) containing chemotherapeutic regimens. Depending upon the treatment protocol, it may develop in over 70% of patients. Early and aggressive corticosteroid treatment leads to improvement in the majority of patients. However, up to 8% of affected patients may fail to respond to corticosteroids and develop progressive respiratory failure leading to death. No alternatives to corticosteroids have thus far been shown useful. We report the symptomatic and physiological improvement of a patient with severe steroid-resistant delayed pulmonary toxicity syndrome, following treatment with interferon-gamma.
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PMID:Interferon-gamma for delayed pulmonary toxicity syndrome resistant to steroids. 1274 74

Treatment of systemic sclerosis has been somewhat haphazard and treatment has often been "borrowed" from the experience gained from treating other connective tissue diseases. There was a period of time that was focused mainly on organ-specific manifestations of systemic sclerosis and some advance in preventing vital organ damage (such as renal crisis) was achieved. The vast improvement in mortality from the use of ACE inhibitors raises one's hopes for other effective therapeutic interventions. At this juncture, the evidence is strong that the ACE inhibitors that are used in scleroderma renal crisis are disease-modifying, even without proving it by a randomized controlled trial. The evidence is strong that the use of epoprostenol for primary pulmonary hypertension is life-saving; however, whether epoprostenol is life-saving in the pulmonary hypertension in scleroderma remains to be proven. There are suggestions that bosentan (for the pulmonary hypertension of scleroderma), cyclophosphamide (for SSc alveolitis), stem cell transplant, interferon-gamma (for interstitial pulmonary fibrosis), and methotrexate (for the skin thickening of diffuse scleroderma) may improve organ function or functional activities, but whether they are truly disease-modifying remains to be proven. As we increase our understanding of the pathophysiology of systemic sclerosis and we learn how better to design trials for systemic sclerosis, we may be more successful in developing optimal disease-modifying therapy. Although the treatment of systemic sclerosis remains difficult, there are an increasing number of potentially effective regimens that are undergoing clinical investigations. A rational approach to therapy seems possible, based on a hypothesis of the pathogenesis of systemic sclerosis. Thus, there is accumulating evidence that supports the use of prostacyclin derivatives to treat systemic sclerosis, some evidence that antifibrotic regimens may be effective, and moderate evidence that immunosuppression also may be effective in certain stages of this disease.
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PMID:Update on disease-modifying antirheumatic drugs in the treatment of systemic sclerosis. 1284 2

Idiopathic pulmonary fibrosis (IPF) is a chronic condition of unknown etiology with an unfavorable outcome from progressively deteriorating respiratory function, leading ultimately to death from respiratory failure. It is characterized by sequential acute lung injury resulting in progressive fixed tissue fibrosis, architectural distortion and loss of function. An excess of profibrotic cytokines and/or a deficiency in antifibrotic cytokines have been implicated in the pathological process as has excessive oxidation. IPF is distinguished from other forms of diffuse pulmonary fibrosis by the presence of the specific histological pattern of usual interstitial pneumonitis. Oral corticosteroids are the usual treatment, but objective response rates are poor and good quality studies do not exist. Other therapies either alone or in combination with corticosteroids are widely used, including azathioprine, colchicine, cyclophosphamide and penicillamine. There is a paucity of good quality information regarding the effectiveness of most noncorticosteroid immunosuppressive agents. Older studies of lesser methodological quality have shown benefits from these drugs, generally when added to corticosteroids. Many were retrospective reviews or uncontrolled, nonrandomized, open-label, prospective studies and often included other histological patterns of disease which are now thought to respond better to immunosuppressive agents. The results of intervention with colchicine and azathioprine have been disappointing when assessed by good quality trials using modern diagnostic criteria. Modern high quality studies are lacking for several agents, notably cyclophosphamide and penicillamine. The older agents may yet prove to be effective but further good quality trials will be necessary to assess these agents adequately. Other new anti-inflammatory, antioxidant, antifibrotic or anticytokine compounds are largely untried or unreported. One trial using interferon-gamma-1b showed a significant improvement in pulmonary function but there are concerns regarding the generalizability of this study. Pirfenidone, cyclosporine and acetylcysteine may also prove to be of benefit but current studies are of insufficient quality to allow for any conclusions to be drawn. Currently there is no good evidence to support the routine use of oral corticosteroids, azathioprine, cyclophosphamide, penicillamine, colchicine, cyclosporine or any other immunosuppressive, antifibrotic or immunomodulatory agent in the management of IPF. Interferon, pirfenidone and other new agents may be of benefit but further studies are required. Any recommendations for treatment must therefore be made on an individual and empiric basis. As some other forms of pulmonary fibrosis may respond better to immunosuppressive agents, it remains important to make an accurate diagnosis, by open lung biopsy if necessary.
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PMID:Idiopathic pulmonary fibrosis: current and future treatment options. 1472 59

GILZ (glucocorticoid-induced leucine zipper), a gene induced by dexamethasone, is involved in control of T lymphocyte activation and apoptosis. In the present study, using Gilz transgenic mice (TG), which overexpress GILZ in the T-cell lineage, we demonstrate that Gilz is implicated in T helper-2 (Th-2) response development. After in vitro stimulation by CD3/CD28 antibodies, peripheral naive CD4+ T cells from TG mice secrete more Th-2 cytokines such as interleukin-4 (IL-4), IL-5, IL-13, and IL-10, and produce less Th-1 cytokines such as interferon-gamma (IFN-gamma) than wild-type mice (WT). CD4+ TG lymphocytes up-regulated Th-2 cytokine expression in the specific response to ovalbumin chicken egg (OVA) antigen immunization. Up-regulation correlated with increased expression of GATA-3 and signal transducer and activator of transcription 6 (Stat6), Th-2-specific transcription factors and decreased expression of T-bet, a transcription factor involved in Th-1 differentiation. Finally, in TG mice delayed-type hypersensitivity, a Th-1 response, was inhibited and bleomycin-induced pulmonary fibrosis, a Th-2 mediated disease, was more severe. These results indicate that Gilz contributes to CD4+ commitment toward a Th-2 phenotype and suggest this contribution may be another mechanism accounting for glucocorticoid immunomodulation.
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PMID:Increased GILZ expression in transgenic mice up-regulates Th-2 lymphokines. 1620 13

Adenovirus pneumonia is uncommon but its severe infection has a mortality as high as 10%, and survivors may have residual airway damages, manifested by bronchiectasis, bronchiolitis obliterans, or pulmonary fibrosis. We report a case of adenovirus pneumonia demonstrating fatal respiratory distress. Adenovirus was isolated from pharyngeal specimens using cell culture and typed as serotype 3 by a combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. The patient characteristically showed hypercytokinemia, characterized by increased levels of lactate dehydrogenase, ferritin, and several cytokines including interferon-gamma and interleukin-6. We treated the patient with pulse methylprednisolne therapy (25 mg/kg/day, for 3 days), resulting in the rapid amelioration of respiratory distress. This is the first report describing the treatment of pulse methylprednisolone therapy in fatal adenovirus pneumonia. During the clinical course, serum Krebs von den Lungen-6 (KL-6), which is a marker for the activity of diffuse interstitial lung disease, was elevated, suggesting that serum KL-6 could be available as a marker of pulmonary prognosis in viral pneumonia.
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PMID:Pulse methylprednisolone therapy in type 3 adenovirus pneumonia with hypercytokinemia. 1663 25

Recent studies have demonstrated that Th2 cytokines, such as interleukin-4 and interleukin-13, enhance fibrotic processes by activating fibroblast proliferation and collagen production, whereas interferon-gamma, a Th1 cytokine, inhibits these processes. Th1 and Th2 cells both differentiate from common T precursor cells, with transcription factor GATA-3 a key regulator of Th2 differentiation. In the present study, therefore, we examined the effects of GATA-3 overexpression on the development of pulmonary fibrosis in a mouse model. Wild-type C57BL/6 mice and GATA-3-overexpressing (GATA-3-tg) mice of the same background were intratracheally treated with bleomycin. The survival rate after bleomycin was significantly decreased in GATA-3-tg mice compared with wild-type mice. The degree of pulmonary fibrosis was much greater in GATA-3-tg mice than in wild-type mice 28 days after bleomycin treatment. Lung interferon-gamma concentration was significantly decreased in GATA-3-tg mice compared with wild-type mice by 7 days after either saline or bleomycin treatment. The concentration of transforming growth factor-beta, a fibrogenic cytokine, was significantly higher in GATA-3-tg mice than in wild-type mice. Exogenous administration of interferon-gamma to GATA-3-tg mice improved the degree of pulmonary fibrosis and thus increased survival. These results indicate that overexpression of GATA-3 enhances the development of pulmonary fibrosis, possibly by reducing interferon-gamma levels in the lung.
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PMID:Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis. 1681 64

The development of bleomycin-induced lung injury, which is a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. Therefore, bleomycin-induced lung fibrosis was examined in E-selectin-/- mice, P-selectin-/- mice, and E-selectin-/- mice treated with anti-P-selectin monoclonal antibody (mAb) in comparison of wild-type mice. E-selectin-/- mice treated with anti-P-selectin mAb exhibited augmented lung fibrosis histologically, increased lung collagen deposition, and increased mortality compared to wild-type mice. Furthermore, lung interferon-gamma mRNA expression decreased in E-selectin-/- mice treated with anti-P-selectin mAb relative to wild-type mice, while tumor necrosis factor-alpha and interleukin-6 mRNA expression increased in these mice. Similar changes were observed in E-selectin-/- mice, albeit to a lesser extent than those treated with anti-P-selectin mAb. Remarkably, flow cytometric analysis revealed that the frequency of interferon-gamma-producing natural killer T (NKT) cells in the bronchoalveolar lavage was decreased in E-selectin-/- mice and E-selectin-/- mice treated with anti-P-selectin mAb compared with wild-type mice. Moreover, the majority of NKT cells expressed high levels of CXCR3, suggesting that NKT cell infiltration is also dependent on CXCR3 expression. These results suggest that E- and P-selectins synergistically inhibit lung fibrosis by promoting the recruitment of NKT cells.
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PMID:E- and P-selectins synergistically inhibit bleomycin-induced pulmonary fibrosis. 1693 51

Enhanced production of collagen is central to fibrotic disorders such as hepatic cirrhosis and pulmonary fibrosis. We describe a sensitive, quantitative, and high-throughput technique for measuring hepatic collagen synthesis in vivo through metabolic labeling with heavy water ((2)H(2)O). Rats and mice received (2)H(2)O in drinking water for up to 35 days. Deuterium incorporation into collagen-bound amino acids (AA) alanine and hydroxyproline (OHP) was measured by gas chromatography-mass spectrometry. A threefold stimulation of collagen fractional synthesis was observed under the maximum dosage of carbon tetrachloride (CCl(4); 1.67 ml/kg). Deuterium enrichment was systematically 20% higher in AA from monomeric collagen relative to dimeric collagen, consistent with slower turnover of the latter. Administration of 1% griseofulvin to mice resulted in a significant, threefold increase in liver collagen synthesis, observable within 12 days and consistent with predicted interstrain differences (C57/Bl6J > BALB/c). Deuterium enrichments of OHP from total liver proteins correlated well with alanine or OHP from isolated collagen. Fibrogenesis subsided after withdrawal of CCl(4) exposure and was reduced to various degrees by coadministration of interferon-gamma, rosiglitazone, atorvastatin, or enalapril. Changes in isotopically measured collagen synthesis correlated with, but were more sensitive and reproducible than, standard histological staining (trichrome) for fibrosis. In summary, liver collagen synthesis can be measured sensitively and with high precision over a short time period, without radioactivity, thereby providing a relatively high-throughput in vivo strategy for rapidly measuring profibrotic activities of suspected hepatotoxicants and antifibrotic activities of drug candidates.
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PMID:Measurement of liver collagen synthesis by heavy water labeling: effects of profibrotic toxicants and antifibrotic interventions. 1734 53

Elevated pulmonary levels of CCL18 have been associated with influx of T lymphocytes, collagen accumulation, and a decline in lung function in pulmonary fibrosis patients. We previously reported that overexpression of CCL18 in mouse lungs triggers selective infiltration of T lymphocytes and moderate lymphocyte-dependent collagen accumulation. We hypothesized that in combination with bleomycin injury, overexpression of CCL18 will worsen the severity of lung inflammation and fibrosis. Mice were infected with a replication-deficient adenovirus encoding CCL18 and then instilled with bleomycin; control mice were challenged with either CCL18 overexpression or bleomycin. Additive effects of CCL18 overexpression and bleomycin injury were observed on pulmonary inflammation, particularly on T-cell infiltration, and increased levels of tumor necrosis factor-alpha, interferon-gamma, matrix metalloproteinase (MMP)-2, and MMP-9. Despite the additive effect on inflammation, CCL18 overexpression unexpectedly attenuated the bleomycin-induced collagen accumulation. Pulmonary levels of active transforming growth factor-beta1 mirrored the changes in collagen levels. Depletion of T cells with antilymphocyte serum or pharmacological inhibition of MMPs with GM6001 abrogated accumulation of collagen and increases in the levels of tumor necrosis factor-alpha, interferon-gamma, and active transforming growth factor-beta1. Thus, CCL18-stimulated T-lymphocytic infiltration is by itself mildly profibrotic to a healthy lung, whereas it partially protects against lung fibrosis in an inflammatory profibrotic pulmonary milieu.
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PMID:Complex regulation of pulmonary inflammation and fibrosis by CCL18. 1756 79

The present study aimed to examine the antioxidant properties of Houttuynia cordata (HC) and its protective effect on bleomycin-induced pulmonary fibrosis in rats. Results showed that aqueous extract of HC exhibited a different magnitude of antioxidant activities in all model systems tested. Although HC showed weaker free radical scavenging and xanthine oxidase inhibitory activity than vitamin E, its anti-lipid peroxidation activity in rat liver homogenate was close to that of vitamin E. In animal studies, HC significantly decreased the levels of superoxide dismutase, malondialdehyde, hydroxyproline, interferon-gamma, and tumor necrosis factor-alpha. However, an increase in the concentration of catalase was noted in the bronchoalveolar lavage fluid. HC also remarkably improved the morphological appearance of the lung of bleomycin-treated rats. These results suggest that HC possesses a protective effect against bleomycin-induced pulmonary fibrosis. Interestingly, this protective effect was more pronounced than that of vitamin E. In conclusion, the protective effect of HC on pulmonary fibrosis could be partly associated with the reduction of oxidative damage caused by bleomycin.
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PMID:Protective effect of Houttuynia cordata extract on bleomycin-induced pulmonary fibrosis in rats. 1759 5


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