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PubMed2002

Halofuginone does not reduce fibrosis in bleomycin-induced lung injury.

Halofuginone, a coccidiostatic alkaloid, has anti-fibrotic properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of halofuginone on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (IT) instillation of 1.2U bleomycin, and intraperitoneal (IP) injection of halofuginone (0.5 mg/dose), every other day; (2) IT 1.2U bleomycin and IP distilled water (D.W.), every other day; (3) IT 0.8U bleomycin and daily IP halofuginone (0.5 mg/dose); (4) IT 0.8U bleomycin and daily IP D.W.; (5) IT saline and IP halofuginone, every other day; (6) IT saline and daily IP D.W.; (7) IT 0.625U bleomycin and oral halofuginone (10 mg/kg rodent lab chow); (8) IT 0.625U bleomycin and standard lab chow. Animals were studied 14 days after IT instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with halofuginone, irrespective of the treatment regimen used. This study does not support the use of halofuginone to prevent or ameliorate lung fibrosis.

Angiogenesis Inhibitors↗
PubMed2000

A comparison of the roles of p53 mutation and AraC inhibition in the enhancement of bleomycin-induced chromatid aberrations in mouse and human cells.

Previous studies have shown that p53 is involved in the repair of bleomycin-induced DNA damage, and that the frequency of bleomycin-induced chromatid aberrations is elevated in G(2)-treated p53 null transgenic mouse embryo fibroblasts (MEF) as compared to isogenic controls. To further characterize p53-mediated DNA repair, we studied the effect of p53 status on the ability of the DNA repair inhibitor 1-ss-D-arabinofuranosylcytosine (AraC) to sensitize MEF to bleomycin-induced chromatid aberrations. Both p53+/+ and p53-/- MEF were treated in G(2) with 0 to 7.5 microg/ml bleomycin in the presence or absence of AraC (5x10(-5) M). The frequency of bleomycin-induced chromatid aberrations was significantly higher in p53-/- cells than wild-type cells in the absence of AraC. AraC treatment significantly increased the frequency of bleomycin-induced chromatid aberrations in p53+/+ MEF to the levels in p53-/- (no AraC) but had no effect in p53-/- MEF. These results suggest that an AraC-sensitive DNA repair component is altered or absent in p53-/- cells. Similar results were observed in p53-mutant WTK1 and wild-type TK6 human lymphoblast cells exposed to 0 to 3 microg/ml bleomycin in G(2). However, AraC did cause a small increase in bleomycin sensitivity in WTK1 cells. This difference from the p53-/- MEF response may be due to differences in p53-mutant phenotype. To determine whether mutation of p53 alters DNA replication fidelity, p53+/+ and p53-/- MEF were exposed to 0 to 1 microg/ml mitomycin C (MMC). MMC did not induce chromosome aberrations in either cell line treated in G(2) but did with the same effectiveness in both cell lines treated in S-phase. Thus, p53 deficiency does not affect DNA replication fidelity or the repair of MMC-induced DNA damage.

Animals↗
PubMed1989

Bleomycin-iron can degrade DNA in the presence of excess ethylenediaminetetraacetic acid in vitro.

The antineoplastic drug bleomycin, when complexed to Fe(II), causes both single- and double-stranded lesions in DNA in vitro. EDTA is commonly used to inhibit the reaction of bleomycin-Fe with DNA, presumably by removing the metal cofactor. In this study, we utilized a simple assay involving the conversion of supercoiled plasmid DNA to the nicked or linear forms to further investigate the ability of bleomycin-Fe to degrade DNA in the presence of EDTA. We found that a 1:1 complex of bleomycin and Fe can degrade plasmid DNA even in the presence of a 10(6) molar excess of EDTA over bleomycin. Furthermore, we found that the half-life for inactivation of bleomycin-Fe by excess EDTA is about 1.5 h. Finally, we demonstrate that excess bleomycin associated with the outer plasma membranes of cells can damage DNA after the cells are lysed in buffers containing EDTA and SDS. These results suggest that EDTA may not be an efficient inhibitor of the reaction of bleomycin-Fe with DNA.

Bleomycin↗
PubMed1998

Stimulatory effect of ascorbate on iron transfer from bleomycin to apotransferrin.

The chemotherapeutic agent, bleomycin, forms a 1:1 complex with both Fe(III) and Fe(II). The rate of ferric ion transfer from bleomycin to apotransferrin is rather slow. However, when ascorbate was added to Fe(III)-bleomycin prior to exposure to apotransferrin, the transfer rate was markedly increased. Ascorbate readily reduces Fe(III)-bleomycin to Fe(II)-bleomycin. A second order rate constant of 2.4 mM-1 min-1 was estimated for this reaction. Fe(II)-bleomycin immediately combines with O2, generating the so-called 'activated bleomycin' complex. The data suggest that a reduced form of iron-bleomycin more readily donates its iron ion to apotransferrin. Reoxidation of ferrous ions, and Fe(III)-transferrin formation occur rapidly.

Antioxidants↗
PubMed1980

Antitumour activity and plasma kinetics of bleomycin by continuous and intermittent administration.

We have studied the cytotoxicity of bleomycin (4--10 u/kg/day for 6 days) given by continuous i.p. infusion (using an osmotic minipump) compared to daily i.p. bolus administration, against P388 leukaemic spleen colony-forming-units(LCFU-S). Continuous i.p. bleomycin at 8 u/kg/day caused a 0.5 log greater reduction of LCFU-S than did an identical dose given by intermittent bolus administration. The infusion minipump provided constant bleomycin plasma levels of 0.62 +/- 0.03 mu/ml and a total plasma AUC (area under the plasma decay curve) of 89.0 mu.h/ml for 6 days at 8 u/kg/day. Intermittent bolus bleomycin at 8 u.kg/day had a terminal-phase plasma t1/2 of 15 min and a total 6-day plasma AUC of 90.8mu.h/ml. These pharmacokinetic data validate the osmotic minipump as a constant drug-delivery system, and suggest that the two administration schedules resulted in equal total bleomycin dosages. Although high peak bleomycin plasma levels (i.e. 32 mu/ml) were achieved with the intermittent bolus administration, continuous-infusion bleomycin's greater inhibition of LCFU-S was probably related to the drug's schedule-dependent cell-killing characteristics. The results of this study provide further rationale for the continuing use of infusion bleomycin schedules in cancer patients.

Animals↗
PubMed2006

Iron is not involved in oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin.

BACKGROUND AND PURPOSE: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stress-mediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. EXPERIMENTAL APPROACH: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H(2)O(2)) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay. KEY RESULTS: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H(2)O(2)/Fe(2+) in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H(2)O(2)/Fe(2+). Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H(2)O(2)/Fe(2+). CONCLUSIONS AND IMPLICATIONS: We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.

Aldehydes↗
PubMed2002

Time course of bleomycin-induced lung fibrosis.

Intratracheal instillation (IT) of bleomycin is a widely used experimental model for lung fibrosis. In this study we describe the time-course of bleomycin-induced lung fibrosis in mice using computer-assisted morphometry. C57Bl/6J mice were treated with a single IT dose of bleomycin or control saline. Animals were killed 3, 6, 14 and 21 days post-IT. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, hydroxyproline concentration in the lung, routine light microscopic examination resulting in a semiquantitative morphological index (SMI) of lung injury, and quantitative morphological measurements (fibrosis fraction and alveolar wall area fraction) aided by optimas image analysis software. Changes in BAL fluid attributed to bleomycin treatment include increased total cell count (days 14 and 21), and increased percentage of neutrophils (days 3 and 6) followed by a sustained increase in lymphocytes (days 6, 14 and 21). Hydroxyproline levels increased in bleomycin-treated mice on days 14 and 21. Median SMI grades were significantly elevated on days 3, 14 and 21. Computer-assisted morphometry demonstrated a 3-fold increase in fibrosis fraction and a 1.3-fold increase in wall area fraction in bleomycin-treated mice on day 14, with no further increase on day 21. These data also demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days after IT instillation of bleomycin, based on the observation that at 14 days the animals developed extensive fibrosis, but had less variability in the fibrotic response and lower mortality than later at 21 days. Computer-assisted morphometry provides objective and quantitative measurements that are a useful tool for the evaluation of bleomycin-induced lung injury.

Animals↗
PubMed2006

Dermojet delivery of bleomycin for the treatment of recalcitrant plantar warts.

BACKGROUND: Plantar warts may cause significant morbidity. Intralesional bleomycin is effective. When bleomycin is injected with a needle and syringe, it is difficult to prevent the bleomycin from infiltrating the dermis adjacent to the wart, producing unnecessary acute pain, persistent pain, and potential sloughing of normal adjacent skin. Efficacy of delivery by dermojet is not yet established. OBJECTIVES: To assess the response of recalcitrant plantar warts to bleomycin delivered by dermojet. METHODS: A total of 47 patients with 138 plantar warts present for more than 2 years and resistant to 10 cycles of cryosurgery, were recruited. Bleomycin (1 U/ml) was delivered intralesionally by dermojet at 5-week intervals for 25 weeks. RESULTS: Out of 138, 124 (89.9%) plantar warts showed complete or partial clearance after one to five sets of bleomycin injections. The recurrence rate was 6/138 (4.4%), and 8/138 (5.8%) warts failed to clear. The reduction in mean surface area of the plantar warts after each set of bleomycin injections compared to baseline surface area was statistically significant. Local side effects were similar to other methods of delivery. No systemic side effects were reported. CONCLUSIONS: This study assesses therapeutic efficacy of bleomycin delivered by dermojet in solely recalcitrant plantar warts. It provides preliminary evidence that this method of delivery may benefit a group of patients with particularly recalcitrant plantar warts and is safe and easy to use in routine dermatology practice.

Antimetabolites, Antineoplastic↗
PubMed1999

Bleomycin versus OH-radical-induced malonaldehydic-product formation in DNA.

PURPOSE: To compare the actions of bleomycin and ionizing radiation on DNA regarding the formation of malonaldehyde-like products. MATERIALS AND METHODS: Calf thymus DNA was treated with iron/bleomycin or gamma-radiation at pH 7. Products were analysed by HPLC. The thiobarbituric-acid reactivity of the samples was determined directly or after HPLC by post-column derivatization. ESI mass spectra were taken on-line following HPLC. RESULTS: Malonaldehyde and malonaldehyde-like products as detected by the sensitive 2-thiobarbituric acid (TBA) assay are formed in gamma-irradiated DNA and thymidine solutions as well as upon treatment of DNA with bleomycin/iron. In gamma-irradiated DNA solutions in the presence of oxygen, no base propenals were detected, and the major TBA-active product was malonaldehyde. In the gamma-radiolysis of thymidine, thymine propenal was formed only in traces (not more than 0.07 per cent of the OH-radical yield). Malonaldehyde was practically absent after treatment with bleomycin; three other TBA-active products were seen by HPLC which have been identified as the cytosine, thymine, and adenine propenals. Guanine propenal was not detected under our conditions. CONCLUSIONS: The absence of these base propenals upon gamma-radiolysis implies that although the initiating step of OH-radical and bleomycin action [i.e. H-abstraction at C(4')] may be the same, the bleomycin-iron complex must participate in subsequent steps en route to the base propenals. It is proposed that the bleomycin pathway may involve the interaction of the C(4')-peroxyl radical with the 'spent' bleomycin-iron complex by ligand exchange, under formation of a bleomycin-iron-peroxyl-radical complex, Blm(Fe4+,*OOR), which then decomposes by heterolysis into the alkoxy cation precursor +OR of the base propenal and reconstitution of the bleomycin-iron complex Blm(Fe,O)3+, i.e. gives rise to base propenal formation without the involvement of a C(4')-hydroperoxide.

Animals↗
PubMed1977

Effect of camptothecin and adriamycin on bleomycin-induced tritiated thymidine triphosphate incorporation in a rat nuclear system.

We investigated the effect of camptothecin and adriamycin on [3H]TTP incorporation and bleomycin-stimulated [3H]TTP incorporation in host liver and hepatoma nuclei of rats. Camptothecin neither stimulated nor inhibited incorporation in the regular nuclear incorporating system. Bleomycin stimulated incorporation to a much greater extent in host liver nuclei and slow-growing hepatomas than it did in the fast-growing hepatoma 7777. Addition of camptothecin to bleomycin stimulated incorporation of [3H]TTP even further. This camptothecin stimulation was slightly greater in hepatoma nuclei than it was in host liver nuclei. Adriamycin inhibited [3H]TTP incorporation in the regular system as well as the bleomycin-induced incorporation. Hepatoma nuclei were more sensitive to this inhibition than were host liver nuclei. Sucrose density gradients indicated that camptothecin caused DNA strand scissions in addition to those produced by bleomycin. Camptothecin alone produced some single-strand but no double-strand scissions. The action of bleomycin was dependent on sulfhydryl-reducing agents. Camptothecin could partially substitute for this requirement. Adriamycin did not produce DNA breaks as determined by neutral or alkaline sucrose density gradients. Despite complete inhibition of bleomycin-induced [3H]TTP incorporation, adriamycin did not prevent bleomycin-induced DNA breaks. The inhibitory effect of adriamycin might have been on the repair system.

Animals↗
PubMed1995

Phase II study of carboplatin and continuous infusion bleomycin followed by cisplatin and 5-fluorouracil in recurrent head and neck cancer.

BACKGROUND: Recurrent squamous cell carcinoma of the head and neck is poorly responsive to most chemotherapy regimens. Carboplatin and bleomycin are effective single agents with non-overlapping toxicity; therefore, we sought to explore the efficacy of this regimen in a phase II study. In the second stage of the study, patients who did not respond to carboplatin and bleomycin were given treatment with cisplatin and 5-fluorouracil (5-FU). PATIENTS AND METHODS: Patients with recurrent squamous cell carcinoma of the head and neck were treated with carboplatin 400 mg/m2 followed by bleomycin 15 units intravenously as a continuous infusion for 4 days. Patients with no tumor response after 3 cycles of carboplatin and bleomycin were crossed-over to receive cisplatin 100 mg/m2 and 5-FU 1000 mg/m2/day continuous infusion for 5 days. RESULTS: Among the 20 carboplatin-bleomycin patients evaluable for toxicity, no cases of grade 4 granulocytopenia were reported and grade 3 or 4 thrombocytopenia developed in only three patients. Three partial responses occurred among the 19 patients (16%) [95% C.I. 0% to 32%] evaluable for response to carboplatin-bleomycin. None of the 11 patients crossed-over to cisplatin and 5-FU had a major response. CONCLUSION: The combination of carboplatin and bleomycin is well tolerated in patients with recurrent head and neck cancer, but the activity does not appear to be superior to the activity of either agent alone. Patients who did not respond to carboplatin and bleomycin were also resistant to the cisplatin and 5-FU regimen.

Adult↗
PubMed1991

Effect of prostaglandin E1 infusion on leukocyte traffic and fibrosis in acute lung injury induced by bleomycin in hamsters.

OBJECTIVE: To determine whether the iv infusion of prostaglandin E1 (PGE1) could modify the early influx of neutrophils into bleomycin-injured lungs and if that would affect subsequent development of inflammation and fibrosis. BACKGROUND AND METHODS: In vivo controlled animal study performed in a university hospital pulmonary research laboratory. Male Syrian golden hamsters (100- to 110-g body weight) were divided into four treatment groups: a) No treatment; b) intratracheal bleomycin plus PGE1 infusion; c) bleomycin plus saline infusion; d) PGE1 infusion only. PGE1 (180 ng/hr.100 g) or saline were infused iv 3 to 25 hr after intratracheal instillation of bleomycin sulfate (0.5 U/0.5 mL.100 g). Total and differential counts of cells recovered by lavage, lavage fluid protein, and lung total protein and hydroxyproline levels were measured from 6 hr to 30 days later. RESULTS: PGE1 infusion reduced the influx of neutrophils 6 hr after bleomycin injury by 53% compared with saline infusion (p less than .0001), but increased inflammatory cell traffic after 24 hr for 15 days. At 4 days, protein recovered in lung lavage fluid was also decreased in PGE1-treated, bleomycin-injured animals, reflecting reduced injury to lung permeability barriers. Accumulation of lung collagen in the PGE1-treated, bleomycin-instilled hamsters tended to be lower than in the bleomycin-injured, saline-infused group at 15 and 30 days, although these differences did not achieve statistical significance. Despite this fact, greater than 33% of the animals in the PGE1-treated group died, possibly indicating an increased risk of sepsis in these animals. CONCLUSIONS: PGE1 infusion can decrease early neutrophil traffic and reduce injury to the lung permeability barriers. However, this treatment augments late inflammatory events and does not significantly alter the development of fibrosis.

Acute Disease↗
PubMed1993

Bleomycin affects cell wall anchorage of mannoproteins in Saccharomyces cerevisiae.

Bleomycin induces strand breakage in DNA through disruption of glycosidic linkages. We investigated the ability of bleomycin to damage yeast cell walls, which are composed primarily of carbohydrate. Bleomycin treatment of intact yeast cells facilitated enzymatic conversion of yeasts to spheroplasts. Bleomycin treatment also altered anchorage of mannoproteins to the cell wall matrix in intact cells or isolated cell walls. Cell surface mannoproteins were labelled with 125I, and their solubilization was monitored. Seventeen hour treatments with bleomycin released some of the label directly into treatment supernatants and facilitated extraction of mannoproteins by dithiothreitol and lytic enzymes. Bleomycin treatments as short as 10 min caused changes in extraction of mannoproteins from intact cells. Specifically, cell wall anchorage of several mannoproteins was affected by the drug. There were drug-induced changes in extractability of mannoproteins with apparent molecular weights of 96,000, 80,000, 61,000, 41,000, 31,500, and 21,000 (determined after deglycosylation with endo-N-acetylglucosaminidase H). The similarity of results obtained in the presence and absence of cycloheximide, the appearance of cell wall effects after only 10 min of treatment, and the similarity of effects in intact cells and isolated cell walls are consistent with direct drug-induced damage and inconsistent with a mechanism dependent on expression of bleomycin-damaged genes or other intracellular mediators. The results are consistent with bleomycin-mediated increases in cell wall permeability through disruption of glycosidic cross-linking structures in the cell wall.

Bleomycin↗
PubMed1992

Effects of bleomycin on growth kinetics and survival of Saccharomyces cerevisiae: a model of repair pathways.

In order to analyze the roles of some repair genes in the processing of bleomycin-induced DNA damage and, especially, the interrelationships among the involved repair pathways, we investigated the potentially lethal effect of bleomycin on radiosensitive mutants of Saccharomyces cerevisiae defective in recombination, excision, and RAD6-dependent DNA repair. Using single, double, and triple rad mutants, we analyzed growth kinetics and survival curves as a function of bleomycin concentration. Our results indicate that genes belonging to the three epistasis groups interact in the repair of bleomycin-induced DNA damage to different degrees depending on the concentration of bleomycin. The most important mechanisms involved are recombination and postreplication repair. The initial action of a potentially inducible excision repair gene could provide intermediate substrates for the RAD6- and RAD52-dependent repair processes. Interaction between RAD6 and RAD52 genes was epistatic for low bleomycin concentrations. RAD3 and RAD52 genes act independently in processing DNA damage induced by high concentrations of bleomycin. The synergistic interaction observed at high concentrations in the triple mutant rad2-6 rad6-1 rad52-1 indicates partial independence of the involved repair pathways, with possible common substrates. On the basis of the present results, we propose a heuristic model of bleomycin-induced DNA damage repair.

Bleomycin↗
PubMed1996

The Saccharomyces cerevisiae IMP2 gene encodes a transcriptional activator that mediates protection against DNA damage caused by bleomycin and other oxidants.

Bleomycin belongs to a class of antitumor drugs that damage cellular DNA through the production of free radicals. The molecular basis by which eukaryotic cells provide resistance to the lethal effects of bleomycin is not clear. Using the yeast Saccharomyces cerevisiae as a model with which to study the effect of bleomycin damage on cellular DNA, we isolated several mutants that display hypersensitivity to bleomycin. A DNA clone containing the IMP2 gene that complemented the most sensitive bleomycin mutant was identified. A role for IMP2 in defense against the toxic effects of bleomycin has not been previously reported. imp2 null mutants were constructed and were found to be 15-fold more sensitive to bleomycin than wild-type strains. The imp2 null mutants were also hypersensitive to several oxidants but displayed parental resistance to UV light and methyl methane sulfonate. Exposure of mutants to either bleomycin or hydrogen peroxide resulted in the accumulation of strand breaks in the chromosomal DNA, which remained even after 6 h postchallenge, but not in the wild type. These results suggest that the oxidant hypersensitivity of the imp2 mutant results from a defect in the repair of oxidative DNA lesions. Molecular analysis of IMP2 indicates that it encodes a transcriptional activator that can activate a reporter gene via an acidic domain located at the N terminus. Imp2 lacks a DNA binding motif, but it possesses a C-terminal leucine-rich repeat. With these data taken together, we propose that Imp2 prevents oxidative damage by regulating the expression of genes that are directly required to repair DNA damage.

Bacterial Proteins↗
PubMed1993

Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice.

BACKGROUND: Increased production of transforming growth factor beta (TGF-beta) seems to have an important role in the pathophysiology of bleomycin induced lung fibrosis. This is attributed to the ability of TGF-beta to stimulate infiltration of inflammatory cells and promote synthesis of connective tissue, leading to collagen deposition. METHODS: The study was designed to evaluate the antifibrotic potential of TGF-beta antibody in mice treated with bleomycin, which is a model of lung fibrosis. Under methoxyflurane anaesthesia, each mouse received intratracheally either 50 microliters sterile isotonic saline or 0.125 units bleomycin in 50 microliters. Within five minutes after the instillation, mice received into the tail vein 100 microliters non-immune rabbit IgG, TGF-beta 2 antibody, or a combination of TGF-beta 2 and TGF-beta 1 antibodies at various dose regimens. Mice were killed 14 days after the instillation and their lungs processed for morphological and biochemical studies. RESULTS: Administration of 250 micrograms of TGF-beta 2 antibody after instillation of bleomycin followed by 100 micrograms on day 5 and 100 micrograms on day 9 significantly reduced the bleomycin induced increases in the accumulation of lung collagen from 445.8 (42.3) micrograms/lung to 336.7 (56.6) micrograms/lung at 14 days. Similarly, the combined treatment with 250 micrograms TGF-beta 2 antibody and 250 micrograms TGF-beta 1 antibody after bleomycin instillation followed by 100 micrograms of each antibody on day 5 also caused a significant reduction in bleomycin induced increases in lung collagen accumulation and myeloperoxidase activity at 14 days. CONCLUSIONS: These results suggest that TGF-beta has an important role in the aetiology of bleomycin induced lung fibrosis; the neutralisation of TGF-beta by systemic treatment with its antibodies offers a new mode of pharmacological intervention which may be useful in treating lung fibrosis.

Animals↗
PubMed2003

Cigarette smoke exposure potentiates bleomycin-induced lung fibrosis in guinea pigs.

The role of tobacco smoking in the development and outcome of pulmonary fibrosis is uncertain. To approach the effects of cigarette smoke on bleomycin-induced lung fibrosis, we studied five groups of guinea pigs: 1) controls, 2) instilled with bleomycin (B), 3) exposed to tobacco smoke for 6 wk (TS), 4) bleomycin instillation plus tobacco smoke exposure for 6 wk (B+TS), and 5) tobacco smoke exposure for 6 wk and bleomycin after smoking (TS/B). Guinea pigs receiving bleomycin and tobacco smoke exposure exhibited higher fibrotic lesions including a significant increase in the number of positive alpha-smooth muscle actin cells compared with bleomycin alone (B+TS, 3.4 +/- 1.2%; TS/B, 3.7 +/- 1.5%; B, 2.3 +/- 1.5%; P < 0.01). However, only the TS/B group reached a significant increase in lung collagen compared with the bleomycin group (TS/B, 3.5 +/- 0.7; B +/- TS, 2.9 +/- 0.4; B, 2.4 +/- 0.2 mg hydroxyproline/lung; P < 0.01). Bronchoalveolar lavage (BAL) from TS/B showed an increased number of eosinophils and higher levels of IL-4 and tissue inhibitor of metalloproteinase-2 (P < 0.01 for all comparisons) and induced a significant increase in fibroblast proliferation (P < 0.05). Importantly, smoke exposure alone induced an increase in BAL neutrophils, matrix metalloproteinase-9, and fibroblast proliferation compared with controls, suggesting that tobacco smoke creates a profibrotic milieu that may contribute to the increased bleomycin-induced fibrosis.

Actins↗
PubMed1993

Expression and secretion of transforming growth factor-beta by bleomycin-stimulated rat alveolar macrophages.

Bleomycin-induced fibrosis in rodents has been used extensively as a model of human pulmonary fibrosis. The influx of monocytes observed during the early stages of fibrosis is at least partially regulated by the elaboration of chemotactic factors in the lung. Exposure of alveolar macrophages (AM phi) to bleomycin either in vivo or in vitro stimulated secretion of monocyte chemotactic activity (MCA). This MCA has been previously characterized as being primarily due to fibronectin fragments. The present experiments revealed that bleomycin also induced AM phi to secrete a second chemotactic factor, transforming growth factor-beta (TGF-beta). However, the TGF-beta secreted by macrophages was in latent form, since no TGF-beta activity was detected unless AM phi conditioned medium (CM) was acid-activated. After acidification, chemotactic activity in CM from AM phi stimulated with bleomycin in vitro was increased by 3.6, whereas activity in AM phi CM from fibrotic rats increased by 2 and that of a bleomycin-stimulated AM phi cell line increased by 1.6. This acid-activatable chemotactic activity was inhibited by antibody to TGF-beta. Bleomycin-stimulated AM phi s secreted significantly more TGF-beta than did unstimulated controls. Further, in vitro exposure of AM phi to bleomycin induced TGF-beta mRNA expression in a time- and concentration-dependent manner, with maximal mRNA being detected following a 16-h incubation with 1 microgram/ml bleomycin.

Animals↗