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)

In two patients with acute leukaemia, the development of progressive interstitial pulmonary fibrosis was observed following chemotherapy with BCNU, Cytoxan and Ara-C. The x-ray changes were accompanied by restrictive changes of pulmonary function and, later on, by severe hypoxia. Serologic tests did not reveal infection with cytomegaly virus or mycoplasma pneumoniae. These findings, together with reports in the literature, suggest a toxic effect of BCNU on the lung. The combination with Cyclophosphamide may contribute to this toxic reaction.
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PMID:[Progressive pulmonary fibrosis during combination chemotherapy with BCNU (author's transl)]. 65 38

Cyclophosphamide is a widely used anticancer drug which damages lung tissue and elicits a progressive fibrotic lesion in mice. The early time course of collagen accumulation and the changes in collagen synthesis which may accompany this lung damage and fibrosis have not been reported. The total lung concentration of hydroxyproline, an index of collagen content and the extent of pulmonary fibrosis, was not significantly increased in mice until 12 days after treatment with 200 mg/kg cyclophosphamide. The change in total lung hydroxyproline content was preceded, on Day 6, by an increase in the rate of acid-insoluble hydroxyproline synthesis. This rate remained elevated to Day 21, but was no longer significantly increased by Day 28. The percentage of total protein synthesis devoted to the production of collagen was significantly increased 9 and 12 days after cyclophosphamide, compared to saline-treated controls. The rate of pulmonary non-collagen protein synthesis was significantly decreased 3 days after cyclophosphamide, and increased 6 and 15 days after this treatment. These data indicate that cyclophosphamide-induced increases in pulmonary collagen synthesis precede the accumulation of this protein. Increased collagen synthesis may occur in the absence of changes in overall protein synthesis although cyclophosphamide also alters non-collagen protein synthesis.
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PMID:Increased pulmonary collagen synthesis in mice treated with cyclophosphamide. 409 21

Thirty-five children with Stage III and IV nonseminomatous malignant germ cell tumors were treated, between June 1, 1977 and December 31, 1982, at Institut Gustave-Roussy, Villejuif, France, and Hospital General de Ninos, Buenos-Aires, Argentina: 11 sacrococcygeal, 12 ovarian, 6 testicular, 5 intrathoracic, and 1 intrabdominal site. All of them had yolk sac component with high level of AFP, seven had also elevated level of HCG. Thirteen patients had primary chemotherapy, 18 received chemotherapy after incomplete surgical excision, and 4 patients with testicular Stage III tumors had chemotherapy immediately following retroperitoneal lymphadenectomy after orchiectomy, because of persistently elevated AFP levels. The chemotherapy regimen for 1 year's duration, repeated every 21 days, and consisted of 6 courses of dactinomycin-Cytoxan (cyclophosphamide) D1 to D5 and vincristine, Adriamycin (doxorubicin) D21, bleomycin D23, and cisplatin D24. Only three patients received complementary radiotherapy. The toxicity of the chemotherapy regimen was severe, but only one death was due to the therapy (pulmonary fibrosis with bleomycin). The number of surviving patients without evidence of disease was 12 of 16 for Stage III and 12 of 19 for Stage IV. The 25-month survival rate was 63% with a follow-up of 11 months to 5.5 years (median, 22 months). This constitutes a dramatic improvement when compared with the survival rate of 21% of 48 similar patients treated at Institut Gustave-Roussy between 1968 and 1977 with surgery, radiotherapy, and chemotherapy (methotrexate, dactinomycin, and Cytoxan).
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PMID:Nonseminomatous malignant germ cell tumors in children. Multidrug therapy in Stages III and IV. 608 96

Interstitial pulmonary fibrosis is described in a 26-year-old woman with malignant lymphoma after prolonged intake of cyclophosphamide. Cyclophosphamide was given over a period of 13 years in an oral daily dose of 50-100 mg. Lung biopsy revealed extensive fibrosis with no evidence of malignancy or infection. Cyclophosphamide is considered the most likely cause of pulmonary fibrosis in this patient.
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PMID:Pulmonary fibrosis after prolonged treatment with low-dose cyclophosphamide. A case report. 684 43

Cyclophosphamide (CYC) is a metabolically activated, DNA-alkylating, antitumor agent that causes pulmonary fibrosis. BALB/cN (B) mice are sensitive and C57Bl/6N (C) mice are resistant to CYC-induced fibrosis. Pulmonary bioactivation may contribute to strain sensitivity. Therefore, we tested the intrinsic susceptibility of murine lung slices to cell injury by direct exposure to CYC for 2-8 hr. Injury was measured by release of lactate dehydrogenase (LDH). DNA damage activates the nuclear enzyme poly(ADP-ribose) polymerase (PAP, EC 2.4.2.30), causing depletion of its substrate, NAD. NAD can also be decreased by phosphorylation to NADP, as seen with oxidative stress. Depletion of NAD can lead to loss of ATP. Thus, we measured LDH release, PAP activation, NAD, NADP and ATP in slices incubated with or without the PAP-inhibitor, 3-aminobenzamide (3-AB). CYC (0.1 to 1.0 mg/mL for 4-8 hr) caused LDH release in slices from both murine strains, but LDH release was significantly greater in B lung slices than in C slices. After an 8-hr incubation 63.9 +/- 3.7% (mean +/- SEM) of total LDH was released from B lung slices with 1.0 mg CYC/mL, whereas only 45.8 +/- 2.6% was released from C lung slices (P < 0.05). 3-AB reduced LDH release to 44.7 +/- 2.4% in B slices and 28.1 +/- 2.0% in C slices (P < 0.05 vs CYC only). PAP activity in nuclei isolated from CYC-treated B lung slices was increased 2- to 4-fold after 2 hr of incubation with 0.5 and 1.0 mg CYC/mL. PAP activation was delayed and reduced with incubation in 3-AB. PAP was activated 2-fold in nuclei from C slices treated with 0.5 mg CYC/mL for 2 hr. NAD was decreased at 2 and 4 hr in B slices treated with 0.5 and 1.0 mg CYC/mL, and at 4 hr with 0.1 mg CYC/mL. NAD depletion occurred only at 4 hr in the resistant C slices treated with 1.0 mg CYC/mL. CYC increased NADP by a similar extent in B and C lung slices. In B slices, NAD losses were approximately 4 times the increases in NADP. CYC did not decrease ATP in B slices and ATP dropped 25% only after 4 hr in the resistant C slices. We conclude that CYC is directly toxic to lung tissue and observe that strain sensitivity in vitro mirrors the sensitivity to fibrosis in vivo. PAP activation and oxidative stress may contribute to this toxicity.
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PMID:Acute pneumocyte injury, poly(ADP-ribose) polymerase activity, and pyridine nucleotide levels after in vitro exposure of murine lung slices to cyclophosphamide. 798 Jun 45

Cyclophosphamide-induced lung toxicity may be difficult to recognize because of the presence of confounding variables such as concomitant use of other cytotoxic drugs, opportunistic infections, diffuse pulmonary malignancy, radiation pneumonitis, and oxygen toxicity. The purpose of this retrospective analysis was to identify the clinical spectrum of pulmonary toxicity of cyclophosphamide. In our review of case records, we sought to identify patients in whom cyclophosphamide was the only identifiable etiologic factor for lung toxicity. In a 20-yr period six patients were identified with cyclophosphamide-induced lung disease, including five men and one woman ranging in age from 42 to 78 yr. Clinical features of toxicity include dyspnea, fever, cough, new parenchymal infiltrates, gas exchange abnormalities on pulmonary function tests, and pleural thickening on chest roentgenogram. Two patterns of cyclophosphamide-induced lung toxicity were identified. A single patient presented with early-onset pneumonitis and responded to discontinuation of the drug. Five patients with late-onset pneumonitis developed progressive pulmonary fibrosis associated with bilateral pleural thickening. Patients with late-onset pneumonitis showed no response to cessation of cyclophosphamide and institution of corticosteroid therapy. Three of these patients died of respiratory failure. Careful review of the individual cases reported in the literature as cyclophosphamide lung toxicity revealed only 12 cases in whom none of the additional confounding factors could be identified. These could easily be divided in the same two categories. Early-onset pneumonitis is reversible and may respond to corticosteroid therapy. Late-onset pneumonitis, frequently associated with pleural thickening, is clinically distinct from idiopathic pulmonary fibrosis but has a chronically progressive course. It appears unresponsive to corticosteroid therapy.
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PMID:Lung toxicity associated with cyclophosphamide use. Two distinct patterns. 897 Mar 80

The Bone Marrow Transplantation Program in Belarus was founded in 1992, and in 1993, a Bone Marrow Transplantation Centre was created in Minsk. From February 1994 to April 1996, 19 allogeneic bone marrow, 16 autologous bone marrow and 10 autologous peripheral blood stem cell transplantations were performed. Reasons for transplantation included chronic myeloid leukemia, multiple myeloma, severe aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, progressive myelofibrosis, Hodgkin's disease, non-Hodgkin's lymphoma, and neuroblastoma. Among the patients were two liquidators involved in the Chernobyl cleanup activity, both of whom underwent allogeneic bone marrow transplantation. A variety of ablative preparative regimens were used, and blood progenitor cells were mobilized by treatment with Cytoxan and granulocyte colony-stimulating factor. Therapy-related deaths resulted from graft-versus-host disease, septic shock, veno-occlusive disease bleeding and intestinal pulmonary fibrosis. Because the transplantation procedures were carried out on people who continued to be exposed to low-level irradiation, the post-transplantation period included a conservative strategy for prevention of graft-versus-host disease. There was nothing unusual about the post-transplantation period, although uncertainty about the continuing radiation dose should be taken into account when interpreting these data.
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PMID:The Chernobyl governmental program: two years of experience at the Belarusian Bone Marrow Transplant Centre. 936 16

Recent studies have brought rich evidence in favour of the significant contribution of the surfactant system-forming structures to morphogenesis of many pulmonary disorders. The aim of this study was to evaluate the effect of intraperitoneal cyclophosphamide administration on changes within this system. The experiments used 40 Wistar rats, of 170 g body weight. The animals were divided into two experimental groups. Group I animals were given cyclophosphamide (Endoxan-ASTA) in a single intraperitoneal dose of 150 mg/1 kg b.w./1 ml PBS/. Group II (control) received 1 ml PBS. All the animals were sacrificed after 1, 3, 7 and 28 days following intraperitoneal cyclophosphamide or PBS administration. Morphological examinations of pulmonary tissue were based on ultrastructural analysis in the transmission electron microscope. The study revealed that a single intraperitoneal cyclophosphamide injection caused damage to all elements forming the surfactant system, particularly to type II alveolar epithelial cells. Rebuilding processes in pulmonary tissue, coexisting with destructive changes, occurred with a significant contribution of type II alveolar epithelial cells. These cells are likely to take an active part in pulmonary fibrosis processes observed after the action of cyclophosphamide.
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PMID:Alveolar cells in cyclophosphamide-induced lung injury. An ultrastructural analysis of type II alveolar epithelial cells in situ. 947 29

The rational treatment of systemic sclerosis can be based on a model of its pathogenesis. This model posits a genetic background upon which external stimulae act, resulting in immune activation, vascular injury, fibroblast proliferation, and collagen deposition. The collagen, in turn, increases immune activation, thus resulting in perpetuation of the activation/injury cycle. If this pathogenetic model holds true, intervention can occur at the level of vascular damage, prevention of fibrosis or immunosuppression. Prevention of vascular damage and improvement of oxygenation has been attempted with prostacyclin derivatives, with mixed results. Prevention of fibrosis with interferon-gamma shows some hopeful results in pulmonary fibrosis. Relaxin, too, seems to hold hope for efficacy, whereas the results of therapy with D-penicillamine have been disappointing. Immunosuppression with chlorambucil has not been effective, but the study design was flawed in that trial. Methotrexate may work, but results are mixed. 5-Fluorouracil seems effective, but may be toxic. Cyclophosphamide is effective in open trials, and well-controlled trials are just starting. Finally, stem cell transplantation, a very aggressive form of immunosuppression, is showing some apparent efficacy, but its use is only in the pilot stages.
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PMID:Rational therapy in the treatment of systemic sclerosis. 1109 5

Pulmonary renal syndrome (PRS), defined as a combination of diffuse pulmonary hemorrhage and glomerulonephritis (GN), represents a severe syndrome for which minimal outcome data are available in the literature. We present a retrospective study of 14 consecutive patients from 1996 to 2000. Mean patient age was 65 +/- 2.1 (SEM) years, and 7 patients were women. At presentation, Po(2) on air was 6.0 +/- 0.5 kPa, and creatinine level was 554 +/- 70 micromol/L. Thirteen patients had systemic vasculitis, and 1 patient had systemic lupus erythematosus (SLE). Five patients were cytoplasmic antineutrophil cytoplasmic autoantibody (C-ANCA) positive, and 7 patients were perinuclear ANCA (P-ANCA) positive; 2 of the latter patients also were positive for anti-glomerular basement membrane antibodies. Renal biopsy was performed in 10 patients. Histological examination showed membranous GN in the patient with SLE and segmental necrotizing crescentic GN in the other 9 patients examined. Twelve of 14 patients were initially dialysis dependent, and 8 of 14 patients required ventilatory support. All patients were treated with corticosteroids, 8 of 14 patients were administered intravenous methylprednisolone, 13 of 14 patients were administered daily cyclophosphamide, and 12 of 14 patients underwent plasma exchange. Patients were followed up for 22 +/- 9 months. Early reduction in cyclophosphamide dosage was required in 9 patients for neutropenia. Seven patients were alive at the end of follow-up, but 5 patients (36%) died in the first month. Of the survivors, 85% and 67% were alive after 1 and 2 years of completed follow-up: 83% and 75% of these survivors were dialysis independent, respectively. Five relapses were seen in 4 patients. One patient died of progressive pulmonary fibrosis. Sepsis was a major factor in 6 of 7 deaths. This patient group was older than those previously reported. Findings confirm previous suggestions that PRS requiring intensive care treatment has high mortality, and early survivors have good 1- and 2-year outcomes. Cyclophosphamide-associated neutropenia and infection were frequent contributors to death, and less toxic alternatives may improve outcome in PRS.
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PMID:Pulmonary renal syndrome: a 4-year, single-center experience. 1177


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