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

Male rats were exposed to single doses (0-30 Gy) of 60Co gamma rays to the right hemithorax. Half of each dose group consumed only control powdered chow after irradiation, and half consumed feed containing 0.10% (w/w) pentoxifylline (50 mg/kg/day). The severity of epilation and desquamation in the field of the radiation port was scored weekly. Two months after irradiation the animals were killed, and pulmonary endothelial function was monitored by the activity of lung angiotensin converting enzyme (ACE) and plasminogen activator (PLA), and by production of prostacyclin (PGI2) and thromboxane (TXA2). The amount of hydroxyproline (HP) in the lung served as an index of pulmonary fibrosis. Radiation produced a dose-dependent decrease in ACE and PLA activity in the right lung and an increase in the production of PGI2 and TXA2. This endothelial dysfunction was accompanied by an increase in wet weight and in protein and HP content in the irradiated lung. Pentoxifylline spared only the increase in lung wet weight and protein content, and actually elevated the radiation-induced hyperproduction of PGI2 and TXA2. The severity of the epilation and desquamation reactions increased with increasing radiation dose and time but was independent of diet. These data indicate that pentoxifylline, despite some promising pharmacological actions, has no beneficial effect on acute radiation reactions in rat lung and skin.
 ...
PMID:Pentoxifylline does not spare acute radiation reactions in rat lung and skin. 172 51

The present study determined whether inhibitors of angiotensin converting enzyme (ACE) can ameliorate radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a range of single doses of 60Co gamma rays to the right hemithorax. Four indices of pulmonary endothelial function were monitored: right lung ACE and plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Hydroxyproline (HP) content served as an index of pulmonary fibrosis. Rats consumed either control powdered chow or feed containing one of five modifying agents continuously after irradiation. The modifiers included three ACE inhibitors: Captopril, CL242817, and CGS13945, respectively, a thiol, a thioacetate, and a nonthiol compound. All of the ACE inhibitors are analogues of proline. Two additional modifiers were tested: penicillamine, a thiol with no ACE inhibitory activity; and pentoxifylline, a vasodilator that is neither a thiol nor an ACE inhibitor. Radiation produced a dose-dependent decrease in lung ACE and PLA activity, and an increase in PGI2 and TXA2 production and in HP content. All ACE inhibitors attenuated the radiation-induced suppression in lung ACE and PLA activity. All thiol or thioacetate compounds ameliorated the radiation-induced increase in PGI2, TXA2, and HP. The two agents that were both thiols and ACE inhibitors (Captopril and CL242817) spared all of the radiation reactions, while the compound that was neither a thiol nor an ACE inhibitor (pentoxifylline) spared none of the reactions. These data suggest a novel application for ACE inhibitors in general, and for Captopril in particular, as modifiers of radiation pneumotoxicity.
 ...
PMID:Radiation pneumotoxicity in rats: modification by inhibitors of angiotensin converting enzyme. 173 1

To determine whether the clinical, immunological and serological features of patients with silica-associated systemic sclerosis are different from patients with the 'idiopathic' form of systemic sclerosis (SS) we studied 22 underground coal miners who were exposed to silica dust (SD), 30 mine workers who later developed silicosis (S) and 17 mine workers exposed to silica dust who subsequently developed a systemic sclerosis-like disease (SA-SS). The patients with SA-SS had features clinically indistinguishable from individual patients with SS. They all had Raynaud's phenomenon, 14 had cutaneous sclerosis identical to that seen in acrosclerosis and three had a generalized cutaneous sclerosis. Sixteen patients had bibasilar pulmonary fibrosis, 10 had necrosis of the fingertip pulps, nine had oesophageal involvement and only one patient had renal involvement. Antinuclear antibodies and circulating immune complexes were detected in three and eight patients with SD, 14 and five patients with S and in 16 and nine patients with SA-SS, respectively. Anti-Scl-70 antibody was detected in eight of the 17 patients with SA-SS. Evidence for in vivo endothelial cell damage, as determined by elevated levels of von Willebrand factor, was found in nine patients with SD, 14 patients with S and in 10 patients with SA-SS. Following incubation of the patient's serum with confluent cultures of human umbilical vein endothelial cells there was only a significant reduction in calcium ionophore-induced release of prostacyclin with the serum from SA-SS patients compared to that with control serum (NC). The mean +/- SEM release of 6-keto-PGF1 alpha (the stable metabolite of prostacyclin expressed as ng/10(4) cells) decreased from 2.90 +/- 0.27 to 2.01 +/- 0.33 (SD), 3.34 +/- 0.42 to 1.76 +/- 0.31 (S), 1.98 +/- 0.12 to 0.64 +/- 0.07 (SA-SS) and 2.28 +/- 0.33 to 1.36 +/- 0.21 (NC) with 1 and 20% serum, respectively. This study demonstrates that immune complex and antinuclear antibody formation and in vivo endothelial cell damage occurs following occupational exposure to silica. The patients who subsequently develop a systemic sclerosis-like disease have clinical, immunological and serological features which are indistinguishable from the idiopathic form of the disease although as a group the SA-SS patients have a higher prevalence of pulmonary involvement and the anti-Scl-70 antibody.
 ...
PMID:Silica-associated systemic sclerosis is clinically, serologically and immunologically indistinguishable from idiopathic systemic sclerosis. 217 91

Twenty-three patients with pulmonary hypertension underwent right cardiac catheterization and measurement of their response to a short-term infusion of prostacyclin. Pulmonary vasodilation with a greater than 20 percent fall in PVR occurred in all five patients with primary pulmonary hypertension where the predominant lesions were plexogenic; in three out of five patients where the predominant lesions were thrombotic; in three out of five patients with pulmonary hypertension and obstruction of proximal vessels; in three out of five patients with COPD; in both patients with pulmonary fibrosis due to sarcoidosis; and in the one patient with pulmonary veno-occlusive disease, where the pulmonary vasodilation was offset by a fall in arterial oxygen content. Prostacyclin is a safe and effective drug to use for testing the response of the pulmonary circulation to a vasodilator in pulmonary hypertension due to different causes. Short-term testing for a vasodilator response, with a view to instituting long-term therapy, should not be restricted to those patients with primary pulmonary hypertension due to plexogenic pulmonary arteriopathy.
 ...
PMID:Pulmonary vasodilation with prostacyclin in primary and secondary pulmonary hypertension. 250 32

Serum copper (Cu) concentration was evaluated as an index of lung injury in two rat models of pneumotoxicity: hemithoracic irradiation and monocrotaline ingestion. In both models there was a dose- and time-dependent increase in serum Cu concentration. This hypercupremia paralleled the development of pulmonary endothelial dysfunction (decreased lung plasminogen activator activity and increased prostacyclin production) and pulmonary fibrosis (hydroxyproline accumulation). In the radiation model, lung injury and hypercupremia persisted for at least 6 months, and were spared similarly when the total dose was delivered in multiple daily fractions as compared to single doses. In irradiated rats, the elevated serum Cu concentration was accompanied by increases in plasma ceruloplasmin, lung Cu concentration, and lung Cu/Zn superoxide dismutase (SOD) activity. In monocrotaline-treated rats, lung damage and hypercupremia also were accompanied by a reduction in liver Cu concentration, and by a direct correlation between the concentrations of Cu and SGOT in the serum. In both models, some but not all modifiers of lung damage (penicillamine, angiotensin converting enzyme inhibitors, pentoxifylline) also partially prevented the insult-induced hypercupremia. In contrast, serum iron concentration was largely independent of treatment in all experiments. These data suggest that elevated serum copper concentration is an accurate and minimally invasive index of lung injury in irradiated and monocrotaline-treated rats.
 ...
PMID:Serum copper concentration as an index of experimental lung injury. 251 9

Three patients underwent single left lung transplantation for end-stage pulmonary fibrosis between June and November 1987. Preoperatively all were housebound, receiving continuous, supplemental oxygen, and their pulmonary function had deteriorated despite corticosteroid and cyclophosphamide therapy. Pulmonary preservation was by means of pulmonary arterial perfusion with modified Euro-Collins solution, 60 ml/kg, at 4 degrees C with adjunctive iloprost (synthetic prostacyclin) infusion. The heart from each donor was used successfully for transplantation. Good early graft function enabled extubation 11, 46, and 96 hours after transplantation. An omental wrap was used around the bronchial anastomosis, and bronchial healing was satisfactory in all. All patients had episodes of pulmonary rejection diagnosed by a combination of symptoms, chest x-ray infiltrates, the exclusion of pneumonitis by bronchoalveolar lavage, and prompt response to "pulse" steroid therapy. Two of the three patients had three episodes of opportunistic pulmonary infections: Herpes simplex pneumonitis, Pneumocystis carinii infection, and Aspergillus pneumonitis. The three patients were discharged from the hospital after 5, 6, and 7 1/2 weeks, respectively. The first and third patients remain alive and well, living essentially normal lives 24 and 19 months after transplantation with no evidence of arterial desaturation on exercise testing while breathing room air. The second patient had symptoms of deteriorating lung function with a progressive decline in forced expiratory volume in 1 second, vital capacity, and diffusion capacity despite repeated "pulse" therapy with combinations of methylprednisolone, antithymocyte globulin, and OKT3 (Ortho Diagnostic Systems Inc., Raritan, N.J.). An open lung biopsy specimen showed obliterative bronchiolitis, and this patient underwent orthotopic lung retransplantation, on the right side. Despite excellent early graft function and early extubation, he died of uncontrolled rejection and general debility after 3 weeks. This early experience in our center with two of three patients surviving 19 to 24 months, respectively, confirms the restoration of good pulmonary function and near normal life-style in patients with end-stage pulmonary fibrosis after single lung transplantation, as first reported by the Toronto Lung Transplant Group. We have used an alternative method of lung preservation (cold crystalloid pulmonary perfusion as opposed to topical cooling, used by the Toronto group), which provided excellent pulmonary preservation up to and beyond 4 hours' storage.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Early results of single lung transplantation in patients with end-stage pulmonary fibrosis. 267 9

The purpose of this study was to evaluate the angiotensin converting enzyme (ACE) inhibitor CL242817 as a modifier of radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a single dose of 60Co gamma rays (0-30 Gy) to the right hemithorax. CL242817 was administered in the feed continuously after irradiation at a regimen of 60 mg/kg/day. Pulmonary endothelial function was monitored by lung ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Pulmonary fibrosis was evaluated by lung hydroxyproline (HP) content. Lung ACE and PLA activities decreased with increasing radiation dose, and cotreatment with CL242817 significantly ameliorated both responses. CL242817 dose-reduction factors (DRF) were 1.3-1.5 for ACE and PLA activity. Lung PGI2 and TXA2 production increased with increasing radiation dose, and CL242817 almost completely prevented both radiation responses. The slope of the radiation dose-response curves in the CL242817-treated rats was essentially zero, precluding calculation of DRF values for PGI2 and TXA2 production. Lung HP content also increased with increasing radiation dose, and CL242817 significantly attenuated this response (DRF = 1.5). These data suggest that the ability of ACE inhibitors to ameliorate radiation-induced pulmonary endothelial dysfunction is not unique to captopril [Ward et al., Int. J. Radiat. Oncol. Biol. Phys. 15, 135-140 (1988)], rather it is a therapeutic action shared by other members of this class of compounds. These data also provide the first evidence that ACE inhibitors exhibit antifibrotic activity in irradiated rat lung.
 ...
PMID:Radiation-induced endothelial dysfunction and fibrosis in rat lung: modification by the angiotensin converting enzyme inhibitor CL242817. 292 77

1. Studies were made to prove that a shift in the eicosanoid metabolism plays a role in the lung-damaging action of paraquat, the active ingredient of Gramoxone, in mice. 2. An attempt was made to inhibit the eicosanoid metabolism with acetylsalicylic acid (Aspisol). Among others, it was found that the metabolic effect impaired by paraquat is influenced in a favourable direction by Aspisol treatment, including the % of survival, the lipid peroxidation values and the superoxide dismutase activity in the lung. 3. At the same time, as a prostacyclin synthesis activator, paraquat participates in the efforts of the organism to eliminate the toxic material, but it later weakens the defence mechanisms by enhancing thromboxane A2 synthesis, and it initiates pulmonary fibrosis, which cannot then be averted with Aspisol.
 ...
PMID:Effects of Gramoxone-induced reactive oxygen radicals on eicosanoid synthesis of mouse lung. 307 35

Plasma thromboxane A2, a vasoconstrictor, and plasma prostacyclin (epoprostenol), a vasodilator, were assessed by double-antibody radioimmunological assay of their respective stable circulating metabolites, thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha, in 9 patients with severe diffuse pulmonary fibrosis (DPF), who were known to become hypo-oxaemic during exercise, and in 9 healthy volunteers. In the 7 patients with the most severe DPF, mean arterial PO2 fell from 68 mm Hg at rest to 51 mm Hg at peak aerobic exercise, and mean TxB2 increased to twice the value at rest. The 9 controls remained oxygen saturated throughout exercise; their mean TxB2 did not change during aerobic exercise, but during anaerobic exercise increased to twice the value at rest, and increased further during recovery. There were no significant changes in 6-keto-prostaglandin F1 alpha in either group. The selective release of TxB2 during aerobic exercise in hypo-oxaemic patients suggests that thromboxane mediates hypoxic pulmonary vasoconstriction. Its release in normal man during anaerobic exercise may reflect a more general response to the metabolic changes of tissue hypoxia.
 ...
PMID:Thromboxane and prostacyclin (epoprostenol) during exercise in diffuse pulmonary fibrosis. 612 94

Previous studies have shown upregulation of lung cell interleukin-6 (IL-6) production in bleomycin-induced pulmonary fibrosis. To further elucidate the regulatory mechanisms governing this disease, the effects of bleomycin on the production of the pleiotropic cytokine, IL-6, were investigated in lung endothelial cells. Rat pulmonary artery endothelial cells were treated with bleomycin at doses previously shown to be effective in upregulating cytokine production in these cells, and the conditioned media was collected and assayed for IL-6 activity. The results show that these endothelial cells constitutively produced IL-6 and that bleomycin increased the production in a time- and dose-dependent manner. Feeding rats diets deficient in n-6 fatty acids is known to ameliorate bleomycin-induced lung fibrosis. In order to examine if fatty acids could modulate IL-6 production in vitro, cells were lipid depleted and then supplemented with 18:1n-9, 18:2n-6, or 18:3n-3 fatty acids, and the effects of bleomycin on IL-6 production reexamined. This regimen resulted in significant depletion of arachidonate in the 18:1n-9 and 18:3n-3 supplemented cells, which was associated with significantly reduced IL-6 production relative to the 18:2n-6-supplemented cells, both constitutively and when stimulated with bleomycin. Preincubation with indomethacin did not significantly inhibit the production of IL-6 by all three groups of cells, nor did supplementation with a stable prostacyclin analog increase IL-6 production. These results suggest that endothelial cell IL-6 production is not directly dependent on prostacyclin or other cyclooxygenase metabolites but may require or be upregulated by 18:2n-6 and/or metabolites derived from it.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regulation of rat pulmonary endothelial cell interleukin-6 production by bleomycin: effects of cellular fatty acid composition. 750 28


1 2 3 Next >>