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PubMed2003

Human SP-A genetic variants and bleomycin-induced cytokine production by THP-1 cells: effect of ozone-induced SP-A oxidation.

Surfactant protein A (SP-A) plays a role in innate host defense. Human SP-A is encoded by two functional genes (SP-A1 and SP-A2), and several alleles have been characterized for each gene. We assessed the effect of in vitro expressed human SP-A genetic variants, on TNF-alpha and IL-8 production by THP-1 cells in the presence of bleomycin, either before or after ozone-induced oxidation of the variants. The oligomerization of SP-A variants was also examined. We found 1) cytokine levels induced by SP-A2 (1A, 1A(0)) were significantly higher than those by SP-A1 (6A(2), 6A(4)) in the presence of bleomycin. 2) In the presence of bleomycin, ozone-induced oxidation significantly decreased the ability of 1A and 1A/6A(4), but not of 6A(4), to stimulate TNF-alpha production. 3) The synergistic effect of bleomycin/SP-A, either before or after oxidation, can be inhibited to the level of bleomycin alone by surfactant lipids. 4) Differences in oligomerization were also observed between SP-A1 and SP-A2. The results indicate that differences among SP-A variants may partly explain the individual variability of pulmonary complications observed during bleomycin chemotherapy and/or in an environment that may promote protein oxidation.

Animals↗
PubMed2005

Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway.

Epithelial cells are considered to be a main target of bleomycin-induced lung injury, which leads to fibrosis in vivo. We studied the characteristics of in vitro bleomycin-induced apoptosis in a mouse lung epithelial (MLE) cell line. Bleomycin caused an increase of reactive oxygen species (ROS) resulting in oxidative stress, mitochondrial leakage, and apoptosis. These were associated with elevated caspase-8 and resultant caspase-9 activity and with upregulation of Fas expression. Glutathione and inhibitors of caspase-8 or caspase-9, but not of FasL, inhibited these effects, suggesting their dependence on ROS, caspase-8 and -9, in a Fas/FasL-independent pathway. However, postbleomycin-exposed MLE cells were more sensitive to Fas-mediated apoptosis. These results demonstrate that the initial bleomycin-induced oxidative stress causes a direct apoptotic effect in lung epithelial cells involving a regulatory role of caspase-8 on caspase-9. Fas represents an amplification mechanism, and not a direct trigger of bleomycin-induced epithelial cell apoptosis.

Animals↗
PubMed1998

Upregulation of alveolar epithelial fluid transport after subacute lung injury in rats from bleomycin.

Alveolar epithelial fluid transport was studied 10 days after subacute lung injury had been induced with intratracheal bleomycin (0.75 U). An isosmolar Ringer lactate solution with 5% bovine serum albumin and 125I-labeled albumin as the alveolar protein tracer was instilled into the right lung; the rats were then studied for either 1 or 4 h. Alveolar fluid clearance was increased in bleomycin-injured rats by 110% over 1 h and by 75% over 4 h compared with control rats (P < 0.05). The increase in alveolar fluid clearance was partially inhibited by amiloride (10(-3) M). Alveolar fluid clearance decreased toward normal levels in rats that were studied 60 days after bleomycin instillation. Remarkably, the measured increase in net alveolar fluid clearance occurred in the presence of a significant increase in alveolar epithelial permeability to protein. Moreover, the increase in alveolar epithelial fluid clearance occurred even though the mRNA for the alpha-subunit of the epithelial sodium channel was decreased in alveolar epithelial type II cells isolated from these rats. In addition, 22Na uptake by isolated alveolar epithelial type II cells from rats treated with bleomycin demonstrated a 52% decrease in uptake compared with type II cells from control rats. Morphological results demonstrated a significant hyperplasia of alveolar type II epithelial cells 10 days after bleomycin injury. Thus, these results provide evidence that proliferation of alveolar epithelial type II cells after acute lung injury may upregulate the transport capacity of the alveolar epithelium, even though the expression of epithelial sodium channels is reduced and the uptake of 22Na per cell is also reduced. These results may have clinical relevance for the resolution of alveolar edema in the subacute phase of lung injury.

Animals↗
PubMed1999

Collagen accumulation is decreased in SPARC-null mice with bleomycin-induced pulmonary fibrosis.

Secreted protein acidic and rich in cysteine (SPARC) has been shown to be coexpressed with type I collagen in tissues undergoing remodeling and wound repair. We speculated that SPARC is required for the accumulation of collagen in lung injury and that its absence would attenuate collagen accumulation. Accordingly, we have assessed levels of collagen in SPARC-null mice in an intratracheal bleomycin-injury model of pulmonary fibrosis. Eight- to ten-week-old SPARC-null and wild-type (WT) mice received bleomycin (0.0035 U/g) or saline intratracheally and were subsequently killed after 14 days. Relative levels of SPARC mRNA were increased 2.7-fold (P < 0.001) in bleomycin-treated WT lungs in comparison with saline-treated lungs. Protein from bleomycin-treated WT lung contained significantly more hydroxyproline (191.9 microg/lung) than protein from either bleomycin-treated SPARC-null lungs or saline-treated WT and SPARC-null lungs (147.4 microg/lung, 125.4 microg/lung, and 113. 0 microg/lung, respectively; P < 0.03). These results indicate that SPARC is increased in response to lung injury and that accumulation of collagen, as indicated by hydroxyproline content, is attenuated in the absence of SPARC. The properties of SPARC as a matricellular protein associated with cell proliferation and matrix turnover are consistent with its participation in the development of pulmonary fibrosis.

Animals↗
PubMed1989

Bleomycin hypersensitivity in dyskeratosis congenita fibroblasts, lymphocytes, and transformed lymphoblasts.

We studied the responses of several dyskeratosis congenita (DC) cell lines to the DNA strand-cleaving and base-damaging agent bleomycin. Fibroblasts, peripheral blood lymphocytes, and transformed lymphoblasts of six DC patients and an obligate DC heterozygote showed more chromatid breaks than did respective controls exposed to various concentrations of bleomycin during the G2 phase of the cell cycle (P less than 0.0001). Unsynchronized DC fibroblasts in culture also showed decreased survival, compared to normals, following bleomycin treatment. DC lymphocytes treated with bleomycin for the final 24 h of culture showed more chromatid- and chromosome-type damage than did normals (P less than 0.0001) or G0-treated DC lymphocytes. Spontaneous chromosome breakage was normal in all six DC cell lines. The ability to distinguish affected and heterozygous DC cells without spontaneous chromosome instability from normals on the basis of their bleomycin hypersensitivity provides a marker for future studies of the pathogenesis of this disorder.

Bleomycin↗
PubMed1987

Role of alveolar phospholipids in bleomycin-induced pulmonary fibrosis in the rat.

The events leading to the onset of the experimental bleomycin-induced pulmonary fibrosis are so far unknown, though recent observations emphasize the crucial role played by lung phospholipids and by alveolar macrophages. In an attempt to verify this point, a series of studies were undertaken by treating rats (CD-COBS) with intratracheal instillation of a single dose of bleomycin (1.5 U). At the same time a group of animals was pretreated with ambroxol (which is known to be a powerful inducer of surfactant production both in fetal and adult type II pneumocytes), 4 mg/kg body weight/day per os, 5 days before the treatment with bleomycin and up to the sacrifice of the animals at the 1st, 3rd, 7th, 14th or 28th day from the instillation. In our experimental model, the 14th day from the treatment with bleomycin seems to be a crucial time since it histologically corresponds to the proliferation of type II pneumocytes; furthermore, an increase of total lecithins in the alveolar spaces was observed, together with an increase of macrophage membrane fluidity. In the ambroxol-pretreated group a partial reduction of the rate of interstitial fibrosis was observed. At the 14th day from treatment the alteration of phospholipid levels was much less pronounced and the microviscosity of alveolar macrophages was similar to that of control animals. These data suggest that the onset of bleomycin-induced pulmonary fibrosis in the rat is characterized by an increase of alveolar lecithins and that this fact could modify the physico-chemical peculiarities of alveolar macrophages. Ambroxol shows a partially protective effect, perhaps by modulating the activity of type II pneumocytes.

Ambroxol↗
PubMed1982

[Tissue specificity of the action of bleomycin. Autoradiographic studies].

The proliferative activity of different types of murine tissue up to 72 h after a single dose of bleomycin was studied via histoautoradiography to determine whether bleomycin has a tissue-specific effect. Bleomycin apparently not only has a general cytotoxic and/or cytostatic action, the strongest being on tissue with a high proliferation rate, but also, as a comparison of the effect of bleomycin on the proliferative activity of squamous epithelium (plantar region, tail, skin, esophagus, tongue) and of mucosal epithelium (stomach, ileum, colon) has indicated, the proliferative activity of squamous epithelium is impaired to a greater extent. This, therefore, distinguishes bleomycin from many other substances used in tumor therapy.

Animals↗
PubMed1985

A case of squamous cell carcinoma treated by intralesional injection of oil bleomycin.

The case of a 70-year-old man with squamous cell carcinoma on the glabella which markedly responded to intralesional injections of oil bleomycin (to a total dose of 115 mg) is reported. Adverse reactions to oil bleomycin comprised fever of 37-38 degrees C immediately after injection, local redness, and swelling and induration of 1-2 months' duration in the marginal area of the injection site. Biopsy of the induration revealed oleogranuloma. The advantages of oil bleomycin are that this dosage form of bleomycin is not accompanied by severe systemic toxicities such as pulmonary fibrosis and that the effective dose is smaller than that of aqueous bleomycin.

Aged↗
PubMed1996

Increased surface tension of the lung and surfactant in bleomycin-induced pulmonary fibrosis in rats.

The increased elastic recoil of the lung in bleomycin-induced pulmonary fibrosis in the rat is due in part to increased surface forces. This study was designed to determine the role of surface tension in situ and in vitro 21 d after instillation of bleomycin. Using sequentially measured pressure-volume curves generated with air, saline, air after lavage with Tween 20, and saline, surface tension was significantly higher in bleomycin-treated lungs than in untreated lungs (4.7 +/- 1.1 versus 1.8 +/- 0.2 dyne/cm, p < 0.01). Surface tension was determined in vitro with a Wilhelmy balance using bronchoalveolar lavage fluid, surfactant, and organic solvent lipid extracts of surfactant. Bleomycin treatment resulted in elevated minimal surface tensions: BALF (20.7 +/- 0.6 versus 13.6 +/- 3.8 dyne/cm, p < 0.02), isolated surfactant (12.0 +/- 1.3 versus 3.0 +/- 0.5 dyne/cm, p < 0.02), and the organic solvent lipid extracted surfactant (11.0 versus 3.2 dyne/cm). These results indicate that the physical properties of surfactant in lungs of rats treated with bleomycin are abnormal and contribute to the increased elastic recoil in this model of pulmonary fibrosis.

Animals↗
PubMed2000

The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice.

Recent studies suggest that Fas-Fas-ligand (FasL) interactions play an important role in the development of lung injury and fibrosis. However, evidence to support this concept is still indirect. To determine whether Fas-FasL interaction is required for the development of bleomycin-induced pulmonary fibrosis in mice, we used Fas-deficient (lpr) and FasL-deficient (gld ) mice as animal models. After intratracheal instillation of bleomycin, we examined the lungs of mice through bronchoalveolar lavage, histologic studies, DNA nick-end labeling, and hydroxyproline assay. The development of cellular infiltrates, bronchiolar and alveolar epithelial apoptosis, and fibrosis following bleomycin instillation in the lungs in lpr mice and gld mice was similar to their development in wild-type mice. The results of this study show that bleomycin-induced pulmonary fibrosis does not require Fas-FasL interaction, and that epithelial cell apoptosis after bleomycin exposure is mediated by Fas-independent pathways.

Animals↗
PubMed1987

Correlation of changes in pulmonary surfactant phospholipids with compliance in bleomycin-induced pulmonary fibrosis in the rat.

Qualitative and quantitative analysis was performed on phospholipids isolated from bronchoalveolar lavage fluid during the development of pulmonary fibrosis in the rat. A single transtracheal injection of 2.0 units of bleomycin was administered to rats to induce lung injury. Animals were killed at 0, 3, 7, 14, 30, and 120 days after bleomycin treatment. Total lipid phosphorus in BAL from animals given bleomycin increased from 1.6 mumol/lung in normal animals to 3.2 mumol/lung at 14 and 30 days. The increase in phospholipids was primarily in phosphatidylcholine with minor increases in phosphatidylinositol and phosphatidylethanolamine. These quantitative changes were accompanied by qualitative changes that included an increase in the percentage of total phosphatidylcholine, disaturated phosphatidylcholine, and phosphatidylinositol. In contrast, the percentage of phosphatidylglycerol was significantly reduced. Plasma phospholipid analysis indicated that these alterations were not due to plasma contamination. The functional significance of the phospholipid changes was assessed by comparing air- and saline-filled compliance measurements at similar times after bleomycin. Abnormal compliance measurements were observed at 3, 7, and 14 days after bleomycin. At 3 and 7 days the predominant compliance defect was at the air-liquid interface; however, at 14 days, when phospholipids were significantly elevated, the defect was primarily due to tissue components.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Bleomycin-induced pulmonary fibrosis. Effects of steroid on lung collagen metabolism.

Using bleomycin-induced pulmonary fibrosis as a model, we have set out to study collagen metabolism in the fibrotic process. As was previously shown, intratracheal administration of bleomycin in the rat caused increased deposition and net synthesis of collagen in the lung. This was accompanied by marked increases in the tissue-free proline pool size and less dramatic increases in the pool's radioactivity when lung mince was pulsed with radioactive proline to measure the net collagen synthesis. Using a technique based on the quantitation of the rate of release of hydroxyproline-containing peptides when lung homogenates were incubated in calcium-containing buffer, lung collagenolytic activity was markedly diminished as a result of bleomycin treatment. Concomitant treatment with the steroid methylprednisolone did not affect significantly this decrease in lung collagenolytic activity. Such steroid treatment, however, prevented the increase in bleomycin-induced lung collagen deposition and partially suppressed total lung collagen synthesis, without affecting the net rate of lung collagen synthesis expressed per mg of DNA. Steroid treatment also inhibited the marked increase in tissue-free proline pool size and radioactivity caused by bleomycin. The mechanism of amelioration of the fibrotic response by the steroid is discussed.

Animals↗
PubMed1982

beta-Aminopropionitrile prevents bleomycin-induced pulmonary fibrosis in the hamster.

beta-Aminopropionitrile (beta APN), an agent that prevents collagen accumulation in tissues, was evaluated for its ability to prevent excess collagen formation in bleomycin-induced pulmonary fibrosis in the hamster. Two groups of animals received a single endotracheal dose of bleomycin; one of these was injected with beta APN twice daily for 30 days. A third group received endotracheal saline and a fourth group received saline and beta APN. After 30 days, we measured pressure-volume curves of saline-filled lungs, collagen content, and degree of fibrosis. Endotracheal bleomycin increased collagen content, decreased lung volume, and produced fibrosis and a mortality rate of 51%. The administration of beta APN to bleomycin-treated animals prevented excess collagen accumulation and diminished total protein, reversed volume diminution, produced less fibrosis, and improved the mortality rate to 24%; beta APN alone had no effect on lung mechanics or collagen content. The biochemical, functional, and structural features of bleomycin-induced lung fibrosis are amenable to control with beta APN.

Aminopropionitrile↗
PubMed1983

Low temperature inhibits bleomycin lung toxicity in the rat.

In order to see if exposure to cold temperature affects the development of bleomycin lung toxicity in mammals, 14 rats received endotracheal injections of bleomycin, while another 14 rats received saline. Half of the saline-treated animals were then exposed to room temperature for 7 days (SRT), and half were exposed to 4 degrees C for 7 days (SC). The bleomycin-treated animals similarly yielded groups kept at room temperature (BRT) and in the cold (BC). After 1 wk the rats were killed and the lungs were sectioned for assessment of histologic changes. All the bleomycin-treated animals had evidence of lung toxicity but this was much less marked in group BC than in group BRT. The lungs in group SC remained normal. These results were confirmed by morphometric methods, which showed significantly increased volume proportions of alveolar walls in groups BRT and BC compared with that in groups SRT and SC (p less than 0.001), with BRT being greater than BC (p less than 0.001). It is concluded that exposure of bleomycin-treated rats to low ambient temperature significantly reduces lung toxicity.

Animals↗
PubMed2006

Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis.

RATIONALE: Discoidin domain receptor 1 (DDR1) is a tyrosine kinase activated by native collagens. Based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 mediates disease progression after lung injury. OBJECTIVES: To investigate the inflammatory and fibrotic responses of DDR1 knockout and wild-type mice to bleomycin-induced lung injury. METHODS: Age- and sex-matched DDR1 knockout and wild-type C57BL/6 mice received a single intratracheal instillation of 2 U/kg bleomycin or saline, respectively. After 2 wk, lung inflammation and fibrosis were assessed using immunohistochemistry, real-time polymerase chain reaction, TUNEL assay, ELISA, fluorescence-activated cell sorting, and Western blot analysis. MEASUREMENTS AND MAIN RESULTS: Compared with wild-type animals, DDR1-null mice were largely protected against bleomycin-induced injury. Bleomycin-induced increases in collagen protein levels and tenascin-C mRNA levels were abrogated in knockout animals. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and a cytokine ELISA. Western blot analysis of injured lung tissue revealed that DDR1-null mice failed to respond to the bleomycin insult with p38 MAPK activation, which was readily observed in wild-type mice. CONCLUSIONS: DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis. Blockade of DDR1 may therefore be a novel therapeutic intervention in patients with pulmonary fibrosis.

Animals↗
PubMed2002

Bleomycin sensitivity of mice expressing dominant-negative p53 in the lung epithelium.

The chemotherapeutic drug bleomycin causes DNA damage and apoptosis in the lungs of mice within hours of endotracheal instillation followed by inflammation and fibrosis weeks later. The p53 tumor suppressor protein mediates cellular responses to DNA damage, including induction of apoptosis, but the effects of p53 activation in the various cell types of the lung during bleomycin-induced pulmonary fibrosis remain unclear. We show here that a transgene with a dominant-negative mutant form of human p53 expressed from the surfactant protein C promoter sensitizes mice to bleomycin-induced lung injury. The bleomycin-exposed transgenic animals display more severe lung pathology with associated collagen deposition and more pronounced lung eosinophilia than simultaneously exposed nontransgenic littermates. These observations suggest that compromising p53 function in the alveolar epithelium impairs recovery of the lung from bleomycin-induced injury.

Animals↗
PubMed1997

Mechanism of impaired local hyaluronan turnover in bleomycin-induced lung injury in rat.

Hyaluronan, a linear polysaccharide, is accumulated in lung interstitium during different pathological conditions, causing interstitial edema and thereby impaired lung function. We investigated the mechanism of local hyaluronan turnover during the early phase of bleomycin-induced fibrotic lung injury in rats. The binding of [3H]hyaluronan to alveolar macrophages (AM) established from bleomycin-treated rats 1 and 5 days after induction of injury was decreased 8- and 15-fold, respectively, compared with that of AM from saline-treated control counterparts, but at day 14 returned almost to the normal level. Data was confirmed by quantitative cytochemistry, using fluorescein-labeled hyaluronan. Analysis of the expression of CD44, a receptor for hyaluronan, by Western blotting revealed a 30% increase of CD44 molecules expressed on AM from bleomycin-treated rats at day 5 compared with control rats. In particular a lower molecular mass form of CD44 appeared. No expression of the receptor for hyaluronan-mediated motility (RHAMM) could be detected. The internalization and degradation of [3H]hyaluronan by AM, obtained from bleomycin-treated rats at days 1, 5, and 14, were decreased about 65%, 35%, and 30%, respectively, compared with AM from the control rats. The AM lysosomal hyaluronidase activity did not differ significantly between bleomycin-treated and control rats. Our results indicate that a decreased hyaluronan binding capacity of AM may account for the impairment of internalization and thereby degradation of excessive hyaluronan during the early phase of fibrotic lung injury.

Animals↗
PubMed2000

Bleomycin-mediated pulmonary toxicity: evidence for a p53-mediated response.

Bleomycin damages DNA and causes lung injury and fibrosis. To determine whether bleomycin is associated with the appearance of DNA damage-inducible proteins, C3H mice received either 0.4 mg bleomycin or normal saline intratracheally and were killed 1 to 14 d later. The lungs were examined for expression of p53, p21(WAF1/PiCl), and proliferating cell nuclear antigen (PCNA) using immunohistochemistry and Western blotting. p53-positive cells first appeared at 5 d after treatment and peaked at 7 d; PCNA-positive cells appeared at 1 d after treatment and peaked at 7 d; and p21-positive cells appeared at 5 d and peaked at 9 d. Western blot analysis confirmed that bleomycin upregulated the DNA damage-inducible proteins in a similar fashion. This is the first evidence that bleomycin causes a p53-dependent response associated with acute injury in the lung.

Animals↗