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PubMed1987

Bronchoalveolar lavage procoagulant activity in bleomycin-induced lung injury in marmosets. Characterization and relationship to fibrin deposition and fibrosis.

Although pulmonary fibrin deposition and coagulation abnormalities have been observed in acute lung injury in humans, their role in the pathogenesis of pulmonary disorders is unclear. In order to gain further insights into the role of the coagulation in lung injury, we examined the relationship between procoagulant activity in bronchoalveolar lavage (BAL) fluids and the evolution of bleomycin-induced lung injury in marmosets. The BAL procoagulant activity was increased at 1, 2, and 4 wk after bleomycin challenge compared with that in control subjects, and it was capable of shortening the recalcification times of plasmas deficient in factor VII and factor VIII but not in factor X. This profile suggested the presence in BAL of an activator of factor X. Activation of purified human factor X by BAL was demonstrated by measuring the amidolytic activity of the generated factor Xa on its N-benzoyl-L-isoleucyl L-glutamyl-glycyl-L-argenine-p-nitroanilide substrate. Factor X activating activity was increased in BAL at 2 wk after bleomycin challenge. Cleavage of 125I-labeled human factor X by BAL from bleomycin-challenged marmosets yielded a 55,500 Mr product that comigrated with factor Xa, the appearance of which correlated strongly with amidolytic evidence of factor Xa activity. Electron microscopy of the lungs of animals from all groups revealed pulmonary fibrin deposition at 2 wk after bleomycin challenge, at the time of increased BAL procoagulant and factor X activating activity. The BAL procoagulant activity was completely sedimentable by ultracentrifugation and was inhibited by concanavalin A and phospholipase C. Activation of purified factor X by BAL was inhibited by monospecific polyclonal goat and rabbit antibodies to human factor VII as well as antibody to bovine tissue factor, demonstrating that factor X activating activity in BAL was attributable to tissue factor associated with material similar to factors VII or VIIa. We conclude that procoagulant activity in BAL increases after bleomycin challenge in marmosets and is attributable to activation of factor X by tissue factor associated with factors VII or VIIa-like material. Increased BAL procoagulant activity is temporally associated with pulmonary fibrin deposition and pulmonary fibrosis during bleomycin-induced pulmonary injury in the marmoset.

Animals↗
PubMed1988

Spontaneous in vitro release of alveolar-macrophage cytokines after the intratracheal instillation of bleomycin in rats. Characterization and kinetic studies.

The intratracheal administration of bleomycin in rats elicits an acute inflammatory response in the lung followed by the development of pulmonary fibrosis. The alveolar macrophage (AM) is a key effector cell involved in this process because of its potential to release a variety of hormonelike molecules (cytokines) that can modulate systemic responses as well as the local response of other lung cells including the interstitial fibroblast. In this report, we have documented the chronology of the in vitro spontaneous release of AM cytokines after a single instillation of bleomycin. We show that supernatants from AM harvested after the administration of bleomycin but not after saline contain lymphocyte-activating factor (interleukin-1) activity. Maximal activity was detected between 6 and 12 h and was barely detectable by Day 7 after bleomycin. In addition, supernatants showing interleukin-1 (IL-1) activity also inhibited the proliferation of log-phase normal rat lung fibroblasts. Fractionation of supernatants from AM harvested 6 h after bleomycin demonstrated that both lymphocyte-activating factor and fibroblast modulatory activity coelute in the same 18-kDa region, suggesting that IL-1 may demonstrate both activities. We also report here the spontaneous release of a second AM cytokine, hepatocyte-stimulating factor, which we have recently shown in humans to be identical to interferon beta 2 and which initiates the hepatic acute-phase protein response. The release of this 30-kDa cytokine from AM of rats exposed to bleomycin has a different chronology than does IL-1, showing a steady increase over time, with maximal activity at Day 28 after bleomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse.

Evidence from divergent sources suggests that some forms of interstitial pulmonary disease are associated with abnormalities of the cellular immune system. To evaluate whether cellular immune processes are necessary determinants for the development of parenchymal alveolitis and fibrosis secondary to bleomycin, we examined the effect of bleomycin on the NIH, outbred white mouse as compared to the homozygous nude, athymic mouse on the NIH outbred background. The nude mouse has virtually no detectable cell-mediated immune function; we therefore hypothesized that if this component of the immune system were necessary for the development of bleomycin-induced interstitial disease, bleomycin would not induce the same pulmonary lesion in the nude mouse as in the white mouse. However, both white and nude mice developed alveolitis and fibrosis after intraperitoneal administration of bleomycin. Comparison of the frequency and severity of these lesions in the 2 groups revealed no significant differences. These findings suggest that the presence of an intact cell-mediated immune system is not an absolute requirement for the development of bleomycin-induced interstitial disease in the mouse. To the extent that this model is an appropriate approximation of human bleomycin-induced pulmonary disease, these results are consistent with the hypothesis that T-lymphocyte mediated processes are not primary determinants of this lesion.

Animals↗
PubMed1982

Differential cellular analysis of bronchoalveolar lavage fluid obtained at various stages during the development of bleomycin-induced pulmonary fibrosis in the rat.

The purpose of this study was to analyze the cellular components of bronchoalveolar lavage fluid throughout the development of bleomycin-induced pulmonary fibrosis in the rat. Animals were killed and lavaged at various times after the administration of a single intratracheal injection of bleomycin. The results demonstrate that a significant influx of inflammatory cells appear in the lavage fluid as early as Day 1 after bleomycin treatment. Polymorphonuclear leukocytes are the first cells to appear and significant concentrations persist for as long as 1 month after bleomycin treatment. There is a very transient yet significant influx of eosinophils on Day 7 after bleomycin treatment. Lymphocytes are present from 3 to 14 days after bleomycin treatment; greater than 97% are T-cells and less than 3% are B-cells. There is a 1:1 ratio of W3/25+ cells (helper cell activity) to OX8+ cells (suppressor cell activity) comprising the lymphocyte population. The blood and lymphoid tissue of these animals contain a normal 2:1 ratio of these subsets. The data demonstrate that specific T-cell populations are present in the air spaces of the lung in response to bleomycin-induced pulmonary fibrosis in this model.

Animals↗
PubMed1999

Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice.

We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased (over saline-treated animals) expression of TNF mRNA in double TNFR knockout (Ko), C57BL/6, BALB/c, and 129/J mice. In contrast, bleomycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregulated expression of the p75 receptor, but not the p55 receptor, in the C57BL/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline content of the lungs after treatment followed this same pattern, with significant increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, whereas bleomycin caused no apparent increases in the BALB/c mice. Even though silica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supports the concept that TNF is a central mediator of interstitial pulmonary fibrosis.

Animals↗
PubMed2001

Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin.

Oxidative stress plays an important role in the development of fibrotic responses in the lung. However, it is not clear whether inhibiting oxidative stress with antioxidants can attenuate fibrotic processes in the lung. The objective of these studies was to test whether the catalytic antioxidant porphyrin manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) could protect mice against bleomycin-induced lung fibrosis. A 10 mg/kg intraperitoneal dose of MnTBAP was established as safe and had a serum and lung half-life of 9.5 h in mice. Based on this data, four groups of mice were given one dose of bleomycin (3.2 U/kg, intratracheal) or saline and MnTBAP (5 mg/kg, intraperitoneal) or saline twice daily for 14 d. Lung fibrosis was assessed by measuring (1) lung hydroxyproline content as an index of collagen accumulation, (2) airway dysfunction by whole body plethysmography, and (3) histopathology. Bleomycin produced a 20% loss in body weight that was only 10% in the bleomycin/MnTBAP group. Bleomycin produced a twofold increase in hydroxyproline content that was decreased 23% by MnTBAP. Bleomycin produced a twofold increase in airway dysfunction that was also attenuated 30% by MnTBAP. Histopathologic analysis of the lungs of mice treated with bleomycin demonstrated a severe fibrotic response that was attenuated 28% by MnTBAP. Future studies on the oxidant mechanisms that MnTBAP is affecting in this bleomycin model of lung fibrosis may shed light on potential new therapeutic approaches for treating interstitial lung diseases.

Animals↗
PubMed2001

Expression of yeast apurinic/apyrimidinic endonuclease (APN1) protects lung epithelial cells from bleomycin toxicity.

Bleomycin is a well-established anti-tumor drug. Its major untoward effect, pulmonary toxicity, has limited its usage. In this study, we used a DNA repair protein, yeast apurinic/apyrimidinic endonuclease (APN1) to reduce the toxicity of bleomycin on lung cells. A549 cells, an alveolar epithelial cell line, were transduced by MIEG3 retroviral vector encoding both enhanced green fluorescent protein (EGFP) and APN1. Transduced cells were sorted by fluorescent-activated cell sorter (FACS) analysis and were cloned. The APN1 expression of transduced A549 cell population and four selected clones expressing different levels of EGFP was confirmed by Northern, Western, and apurinic/apyrimidinic (AP) endonuclease activity analyses. The expression of APN1 was positively correlated with the expression of EGFP. The protective effect of APN1 against bleomycin was determined by single cell gel electrophoresis/Comet assay and by clonogenic survival assay following bleomycin treatment. The A549 population expressing APN1 showed a significant reduction of DNA damage in the presence of 20, 50, and 100 microg/ml bleomycin; similarly, the APN1-expressing A549 population also demonstrated increased survival in the presence of bleomycin compared with the vector-transduced A549 population. In selected clones, three of four APN1-expressing clones resulted in significantly improved cell survival. The current study suggests that the yeast DNA repair protein, APN1, can reduce bleomycin toxicity to target lung cells.

Bleomycin↗
PubMed1993

Regulation of rat pulmonary endothelial cell interleukin-6 production by bleomycin: effects of cellular fatty acid composition.

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)

Animals↗
PubMed2003

Role of repeated lung injury and genetic background in bleomycin-induced fibrosis.

Current hypotheses of the pathogenesis of many forms of pulmonary fibrosis suggest that (i) a stimulus results in repeated or prolonged episodes of lung injury, and (ii) genetic factors modulate the outcome of the injury. The commonly employed single-exposure bleomycin model results in only temporary fibrosis. Therefore, we evaluated whether repeated bleomycin exposures, in the setting of a genetic background more likely to develop a T helper 2 (Th2) response, would induce prolonged fibrosis. Lung fibrosis was induced by intratracheal bleomycin injection, either as a single exposure or as three consecutive exposures. We found that bleomycin induced a Th2-like environment in both Th1-biased C57BL/6J and Th2-biased DBA/2 mice. We also found histologic changes and collagen increases consistent with lung injury/fibrosis at early time points, but prolonged fibrosis only after multiple exposures in the Th2-biased DBA/2 mice. We also determined if impaired healing of bleomycin-induced injury would prolong fibrosis in the C57BL/6J mice. Endothelial nitric oxide (which protects endothelial cells from oxidant-induced injury) synthase knockout animals on a C57BL/6J background also had prolonged fibrosis, similar to DBA/2 mice, after multiple bleomycin exposures. This was specific to eNOS, as inducible nitric oxide synthase knockout animals cleared the fibrosis as effectively as wild-type C57BL/6J mice. This data indicate that healing of injury/fibrosis after bleomycin is complex and can be determined by a number of genetic and environmental factors.

Animals↗
PubMed1978

Bleomycin-induced diffuse interstitial pulmonary fibrosis in baboons.

Pulmonary fibrosis was induced in eight baboons with bleomycin; five untreated animals were controls. After 45-65 U/kg of bleomycin, lung volumes and diffusing capacity were reduced, and static lung pressure-volume curves were shifted to the right. Right middle lobes were resected at this time in five bleomycin-treated and two control animals. Compared to controls, right middle lobes from bleomycintreated animals had increased weight and contained increased amounts of total protein, collagen, elastin, and DNA; synthesis of collagen and noncollagen protein were also elevated. Occasional alveolar septae were edematous and infiltrated by mononuclear inflammatory cells; a slight increase in collagen was demonstrable histologically. Four of six treated animals died with extensive diffuse interstitial fibrosis after 95 U/kg of bleomycin. Biochemical analyses revealed significantly elevated lobar contents of dry weight, protein, elastin, and collagen. Two animals survived 95 U/kg of bleomycin and were terminated 6 mo after treatment. In these animals, physiologic studies were indicative of restrictive lung disease, but lung histology was nearly normal. Lung weight, total protein, and DNA had returned to control values, but collagen and elastin were increased in amount and concentration. Bleomycin induces an intense inflammatory response in the lung. During this inflammation, connective tissue proliferation occurs in concert with proliferation of other tissue components. Cessation of bleomycin treatment is followed by resolution of inflammation manifested by decreases in tissue mass, cellular content, and nonconnective tissue protein. Collagen and elastin deposited during inflammation are less successfully removed during resolution, leading to a stage characterized by increased concentrations of these proteins. A similar sequence of tissue alterations may occur in idiopathic diffuse interstitial fibrosis of man in response to various lung injuries.

Animals↗
PubMedDate not supplied

TIMP-1 is a key factor of fibrogenic response to bleomycin in mouse lung.

Pulmonary fibrosis is characterized by the excessive deposition of extracellular matrix in the interstitium, resulting in respiratory failure. The role of remodeling mediators such as metalloproteinases (MMPs) and their inhibitors (TIMPs) in the fibrogenic process remains misunderstood. We investigated MMP-9, MMP-2, TIMP-1, TIMP-2 and TIMP-3 in the fibrotic response to bleomycin of fibrosis prone C57BL/6J and fibrosis resistant BALB/c mice. Mice were administered with 0.1 mg bleomycin by intranasal administration. Either 24 h or 14 days after, the mice were anesthetized and underwent either bronchoalveolear lavage (BAL) or lung removal. Collagen deposition in lung tissue was determined by hydroxyproline measurement, MMP activity was analyzed by zymography, and other mediators were analyzed by ELISA. TIMP-1 was localized in lung sections by immunohistochemistry and real time PCR was performed to gene expression in lung. Non parametric Mann-Whitney and Spearman tests were used for statistical analysis. Fourteen days after bleomycin administration, hydroxyproline assay and histological study revealed that BALB/c mice developed significantly less fibrosis compared to C57BL/6J mice. At day 1, bleomycin enhanced TIMP-1, MMP-2 and MMP-9 protein levels in BALF, and induced corresponding genes in lung tissue of both strains. The rise of Timp-1, Mmp-9 and Mmp-2 gene levels were significantly stronger in lungs of C57BL/6J, whereas gelatinase activities of MMP-2 and MMP-9 were similar. Immunohistochemistry revealed that TIMP-1 macrophages and epithelial cells were prominent TIMP-1 producers in both strains. At day 14, neither MMP-2 nor MMP-9 levels exhibited strain-dependent protein level or gene expression, although TIMP-1 was strongly associated with fibrosis. Interestingly, bleomycin induced neither Timp-2 nor Timp-3 in lung tissue at any time of the study. The present study shows that early altered regulation of TIMP-1 following bleomycin administration may be involved in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed2003

Bleomycin induces cellular senescence in alveolar epithelial cells.

Cellular senescence is a state of irreversible growth arrest. In this paper the authors examined whether bleomycin, an agent that causes pulmonary fibrosis, induces the senescence of alveolar epithelial cells. Type II-like alveolar epithelial (A549) cells or rat primary type II cells were exposed to bleomycin and then evaluated for markers of cellular senescence. Bleomycin was also administered intratracheally in C57BL/6 mice. The authors found that exposure to bleomycin induced cellular senescence in A549 cells and rat primary type II cells. The senescence was characterised by a dose- and time-dependent increase in senescence-associated beta-galactosidase activity, senescence-associated changes in cell morphology, an increase in cell size and lysosomal mass, the overexpression of p21 protein, and irreversible growth arrest. The intratracheal injection of bleomycin in mice induced an increase in senescence-associated beta-galactosidase activity in type II epithelial cells, reaching a maximum at day 7. These results suggest that bleomycin induces a phenotype that is indistinguishable from that of senescence in alveolar epithelial cells. The induction of epithelial senescence by bleomycin may contribute to the pathway of impaired re-epithelialisation leading to pulmonary fibrosis.

Animals↗
PubMed2003

Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.

Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.

Acetylcysteine↗
PubMed2005

Inhibition or knock out of inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury.

BACKGROUND: In the present study, by comparing the responses in wild-type mice (WT) and mice lacking (KO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of on the lung injury caused by bleomycin administration. When compared to bleomycin-treated iNOSWT mice, iNOSKO mice, which had received bleomycin, exhibited a reduced degree of the (i) lost of body weight, (ii) mortality rate, (iii) infiltration of the lung with polymorphonuclear neutrophils (MPO activity), (iv) edema formation, (v) histological evidence of lung injury, (vi) lung collagen deposition and (vii) lung Transforming Growth Factor beta1 (TGF-beta1) expression. METHODS: Mice subjected to intratracheal administration of bleomycin developed a significant lung injury. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from bleomycin-treated iNOSWT mice. RESULTS: The intensity and degree of nitrotyrosine staining was markedly reduced in tissue section from bleomycin-iNOSKO mice. Treatment of iNOSWT mice with of GW274150, a novel, potent and selective inhibitor of iNOS activity (5 mg/kg i.p.) also significantly attenuated all of the above indicators of lung damage and inflammation. CONCLUSION: Taken together, our results clearly demonstrate that iNOS plays an important role in the lung injury induced by bleomycin in the mice.

Animals↗
PubMed2005

Radiosensitising effect of electrochemotherapy with bleomycin in LPB sarcoma cells and tumors in mice.

BACKGROUND: Bleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug. The aim of the study was to evaluate whether a physical drug delivery system - electroporation can increase radiosensitising effect of bleomycin in vitro and in vivo. METHODS: LPB sarcoma cells and tumors were treated either with bleomycin, electroporation or ionizing radiation, and combination of these treatments. In vitro, response to different treatments was determined by colony forming assay, while in vivo, treatment effectiveness was determined by local tumor control (TCD50). Time dependence of partial oxygen pressure in LPB tumors after application of electric pulses was measured by electron paramagnetic oxyimetry. RESULTS: Electroporation of cells in vitro increased radiosensitising effect of bleomycin for 1.5 times, in vivo radiation response of tumors was enhanced by 1.9 fold compared to response of tumors that were irradiated only. Neither treatment of tumors with bleomycin nor application of electric pulses only, affected radiation response of tumors. Application of electric pulses to the tumors induced profound but transient reduction of tumor oxygenation. Although tumor oxygenation after electroporation partially restored at the time of irradiation, it was still reduced at the level of radiobiologically relevant hypoxia. CONCLUSION: Our study shows that application of electric pulses to cells and tumors increases radiosensitising effect of bleomycin. Furthermore, our results demonstrate that the radiobiologically relevant hypoxia induced by electroporation of tumors did not counteract the pronounced radiosensitising effect of electrochemotherapy with bleomycin.

Animals↗
PubMed2005

Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma.

PURPOSE: Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients. PATIENTS AND METHODS: One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology. RESULTS: BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS. CONCLUSION: BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age > or = 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.

Adolescent↗
PubMed1989

Effects of photo-activated bleomycin on deoxyribonuclease I, exonuclease III and deoxyribonucleic acid polymerase I reactions.

The activity of bleomycin to break the strand of deoxyribonucleic acid (DNA) in the presence of 2-hydroxy-1-ethanethiol (2-mercaptoethanol) was enhanced by ultraviolet (UV) irradiation. Photo-activated bleomycin stimulated the action of deoxyribonuclease I (DNase I) to degrade DNA and the DNA synthesis by DNA polymerase I with DNase I. On the other hand, although UV-irradiated bleomycin scarcely broke the DNA strand in the presence of 1,2-benzenediol (catechol), it stimulated the action of DNase I to degrade DNA in the presence of catechol. In accordance with the inhibition by catechol, when DNA treated with UV-irradiated bleomycin in the presence of catechol was employed as a primer for the DNA synthesis, the incorporation of precursor into the acid-insoluble fraction by DNA polymerase I with exonuclease III was reduced to about one-half of the incorporation into DNA treated with unirradiated bleomycin. These findings suggest that the ability of bleomycin to bind to double-helical DNA forming regions sensitive to DNase I was increased by an appropriate dose of UV irradiation and that catechol inhibited the activity of the UV-irradiated bleomycin to break the DNA strand rather than to bind to DNA.

Bleomycin↗
PubMed1990

Bleomycin-induced lung injury in the rat: effects of the platelet-activating factor (PAF) receptor antagonist BN 52021 and platelet depletion.

Bleomycin is a highly effective antitumor agent, but pulmonary toxicity, characterized by an acute inflammatory reaction and associated pulmonary edema, limits clinical use of the drug. Platelets and platelet-activating factor (PAF), a membrane-derived phospholipid, have been implicated in the mechanisms that can mediate pulmonary microvascular injury. We sought to investigate the role of PAF in bleomycin-induced lung injury in the rat, using the PAF receptor antagonist BN 52021; and the role of platelets though the use of an anti-platelet antibody. Lung injury was induced by intratracheal bleomycin (1.5 mg) and assessed by measurements of lung wet weight and total pulmonary extravascular albumin space (TPEAS). Bleomycin caused a significant increase in both indices after 48 hr, compared with control animals (p less than 0.05). A single dose of BN 52021 (20 mg/kg orally) significantly reduced the bleomycin-induced increase in lung weight, but not the rise in TPEAS (p greater than 0.05). Increasing the dose of BN 52021 (20 mg/kg/12 hr, orally) had no additional effect. Reducing circulating platelet numbers by approximately 75% had no effect on either the increase in lung weight or TPEAS, observed 48 hr after bleomycin (p greater than 0.05). PAF may partially contribute to the acute inflammatory reaction seen after intratracheal bleomycin in rats.

Administration, Inhalation↗