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PubMed1983

The effects of the nude (nu/nu) mutation on bleomycin-induced pulmonary fibrosis. A biochemical evaluation.

Previous reports have suggested that the immune system is involved in the lung fibrogenic response to certain agents or treatments. In the present study, we have evaluated the impact of the athymic (nude) mutation on the development of pulmonary fibrosis in mice induced by a single intratracheal instillation of bleomycin (0.75 units/animal). Histologic examination revealed that cellular infiltration, fibroblast proliferation, and connective tissue accumulation were diminished in the nude mice when compared with euthymic (het) control mice. In contrast to control animals treated with saline, total lung hydroxyproline in the nude mouse was not significantly increased at 14 and 30 days after bleomycin treatment. Net collagen synthesis, as assessed by measuring the rate of incorporation of tritiated proline in an organ culture system, was increased above control values in both nude and euthymic mice at 14 days after bleomycin treatment, although these values returned to normal at 30 days. However, lung collagen synthetic rates, normalized to dry lung weights, were significantly higher at 14 days in euthymic bleomycin-treated control mice than in the nude bleomycin-treated animals. The data indicate that the nude athymic mutation protects, at least partially, against bleomycin-induced pulmonary fibrosis, thus suggesting a role for the cellular immune system in regulating the fibrogenic response to this drug.

Animals↗
PubMed2002

Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice.

To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in gamma-glutamyl transpeptidase (GGT-/-), a key enzyme in glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type mice as judged by a near absence of neutrophils in lung tissue and bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9. Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/- 756 versus 1975 +/- 817, p < 0.01). Lung collagen content revealed a significant increase in bleomycin-treated wild-type (15.1 +/- 3.8 versus 8.5 +/- 0.7 microg hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 +/- 1.7 versus 8.8 +/- 0.8). Control lungs from GGT-/- showed a significant reduction of cysteine (0.03 +/- 0.005 versus 0.055 +/- 0.001, p < 0.02) and GSH levels (1.24 +/- 0.055 versus 1.79 +/- 0.065, p < 0.002). These values decreased after 72 hours of bleomycin in both GGT-/- and wild-type but reached their respective control values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings suggest that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury.

Acetylcysteine↗
PubMed1994

Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats.

To investigate the potential role of transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGF-R) in the fibroproliferative response to acute lung injury, we determined lung steady-state TGF-alpha and EGF-R mRNA levels, TGF-alpha protein levels, and the distribution of TGF-alpha and EGF-R immunoreactive protein of bleomycin-injured and control rat lungs. At 2 and 4 days after a single intratracheal injection of bleomycin, TGF-alpha mRNA levels increased to 159% and 184% of control values, respectively. EGF-R mRNA levels increased to 163%, 314%, and 170% of control values at 1, 7, and 14 days after bleomycin instillation. TGF-alpha protein levels in whole lung extracts increased to 230% of control values at 4 days after bleomycin administration. TGF-alpha and EGF-R immunoreactivity was detected in macrophages, alveolar septal cells, and airway epithelium of control and bleomycin-injured animals with an apparent increase in the intensity and number of specifically immunostained cells following lung injury. TGF-alpha and EGF-R immunoreactive proteins were detected in foci of cellular proliferation and in areas of intraalveolar fibrosis. We conclude that TGF-alpha and the EGF-R are present in normal and bleomycin-injured rat lung and that the expression of this growth factor and its receptor are up-regulated following lung injury. These results suggest that increased expression of TGF-alpha and the EGF-R may be an important mechanism that modulates the fibroproliferative response to acute lung injury.

Amino Acid Sequence↗
PubMed2001

Selective induction of tissue inhibitor of metalloproteinase-1 in bleomycin-induced pulmonary fibrosis.

Tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that have the capacity to modify cellular activities and to modulate matrix turnover. We demonstrate that TIMP-1 messenger RNA (mRNA) and protein expression are selectively and markedly increased in a murine model of bleomycin-induced pulmonary fibrosis. Northern analysis showed that lung steady-state TIMP-1 mRNA levels increased 14-fold after bleomycin administration compared with control mice. Expression of the genes for TIMP-2, TIMP-3, and interstitial collagenase (matrix metalloproteinase-13) was unaltered in the injured lung. In situ hybridization demonstrated that TIMP-1 gene induction was spatially restricted to areas of lung injury. Metalloproteinase inhibitory activity of relative molecular mass of ~ 21 to 28 kD, corresponding to the molecular weights for TIMP-1 and TIMP-2, was identified in lung extracts of bleomycin-injured mice by reverse zymography. Western analysis demonstrated that TIMP-1 protein levels in bronchoalveolar lavage fluid (BALF) of bleomycin-treated mice increased 220- and 151-fold at Days 4 and 28, respectively, compared with control mice. TIMP-2 immunoreactive protein in the BALF increased 20- and 103-fold relative to controls at Days 4 and 28, respectively. These results demonstrate that TIMP-1 gene expression is selectively increased, and that the expression of TIMP-1 and TIMP-2 is differentially regulated in bleomycin-induced pulmonary fibrosis. The profound and durable increase in TIMP-1 and TIMP-2 proteins suggests an important regulatory role for these antiproteases in the inflammatory and fibrotic responses to bleomycin-induced lung injury.

Animals↗
PubMed2001

Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor.

Pulmonary fibrosis is a progressive disorder characterized by the loss of alveolar architecture through epithelial and endothelial cell apoptosis and fibroblast proliferation. Recent studies showed that angiotensin-converting enzyme (ACE) activity is increased in fibrotic tissues, and ACE inhibitors administered in vivo ameliorate fibrosis, suggesting that ACE may play a critical role. However, the regulation of ACE expression is not well understood. In the present study, we demonstrate that bleomycin, a chemotherapeutic agent which induces pulmonary fibrosis in animals and humans, increases gene expression of ACE. Treatment of primary bovine pulmonary artery endothelial cells with 0.1 to 1.0 microg/ml bleomycin increased ACE enzymatic activity and ACE mRNA, as monitored by hippuryl-L-histidyl-L-leucine assay and competitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Luciferase reporter constructs showed that upregulation of ACE transcription by bleomycin is mediated through element(s) in the 97-bp ACE promoter. Bleomycin activated p42/p44 mitogen-activated protein kinase (MAPK) and induced nuclear translocation and activation of the early growth response (Egr)-1 transcription factor, a factor previously shown to positively regulate ACE expression. The MAPK kinase1/2 (MEK1/2) inhibitor U0126 blocked MAPK and Egr-1 activation by bleomycin, suggesting that Egr-1 activation is MAPK dependent. These data provide the first evidence that bleomycin activates ACE gene expression through the MAPK pathway and Egr-1.

Animals↗
PubMed1989

Bleomycin induces the hsp 70 heat shock promoter in cultured cells.

Bleomycin-induced lung disease is characterized by cell injury followed by fibroblast proliferation. Cells respond to injury by synthesizing a family of heat shock proteins. These proteins are critical to cell survival, and those of the 70,000 MW group (hsp 70) are essential for cell division and proliferation. To evaluate the effect of bleomycin on heat shock gene expression, we transfected a gene construct containing the hsp 70 heat shock gene promoter into fibroblasts. Doses of bleomycin, which have previously been shown to augment lung fibroblast proliferation, induce the hsp 70 heat shock promoter in the transfected cells. Bleomycin did not induce the expression of a non-hsp promoter placed in cells as a control of nonspecific gene activation. These observations suggest that bleomycin exposure may cause significant alterations in important DNA promoter regions such as the hsp 70 promoter and point to new ways to assess bleomycin-induced changes in cells.

Animals↗
PubMed2003

Increased basigin in bleomycin-induced lung injury.

Basigin is expressed in many tissues during development, including lung. It is also found on tumor cells and in wounds where it is thought to stimulate adjacent fibroblasts to produce matrix metalloproteinases. To investigate whether basigin might be expressed in fibro-inflammatory lung processes, we generated bleomycin-induced lung injury in mice. At 14 d after intratracheal bleomycin, we found basigin prominently in areas of fibrosis, alveolar macrophages, and bronchiolar epithelium, whereas it was only weakly present in bronchiolar epithelium in untreated mice. Western blots of radioimmunoprecipitation assay RIPA-insoluble fractions of bleomycin-treated lungs showed increased basigin compared with RIPA-insoluble fractions of lung from untreated mice. By quantitative reverse transcriptase-polymerase chain reaction, lung basigin mRNA was significantly increased 14 d after bleomycin, and by in situ hybridization, basigin mRNA was prominent in bronchiolar epithelium. Western blots of bronchoalveolar lavage fluid (BALF) showed various forms of basigin after bleomycin that were not present in BALF from untreated lung. These results demonstrate that bleomycin-induced lung injury is associated with increased basigin expression in bronchiolar epithelium, deposition of basigin in fibrotic sites, and increased basigin in BALF. Accordingly, basigin may play a role in diffuse alveolar injury.

Animals↗
PubMed1991

Stimulation of rat endothelial cell transforming growth factor-beta production by bleomycin.

This study examines the hypothesis that mediators from lung endothelial cells could promote lung collagen synthesis in pulmonary fibrosis. Since bleomycin induces pulmonary fibrosis in humans and animals, the effects of this drug on endothelial cells were examined. Endothelial cell conditioned media were prepared in the presence of various doses of bleomycin, and tested for their ability to stimulate lung fibroblast collagen synthesis. The results show a dose-dependent stimulation of endothelial cell secretion of collagen synthesis stimulatory activity by bleomycin, which peaked at a dose greater than or equal to 100 ng/ml. Stimulation was selective for collagenous protein synthesis. Gel filtration analysis showed most of the activity to reside in fractions with an estimated molecular mass range of 10-27 kD. The activity was inhibited by anti-transforming growth factor-beta (TGF-beta)antibody, but not by nonimmune control IgG. The presence of TGF-beta was confirmed using the mink lung epithelial cell assay. Northern blotting revealed significant increases in TGF-beta mRNA in bleomycin-stimulated endothelial cells. Thus in vitro stimulation of endothelial cells by bleomycin upregulates TGF-beta production, presumably by increased transcription. In view of the chemotactic and matrix synthesis stimulatory properties of this cytokine, such an increase in TGF-beta production may play an important role in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed1993

Regulation of alveolar macrophage transforming growth factor-beta secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat.

In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we previously demonstrated that TGF-beta was markedly elevated within 7 d of bleomycin administration. At the time of maximal TGF-beta production, TGF-beta 1 was localized by immunohistochemistry to be present almost exclusively in alveolar macrophages. In this study, we have demonstrated that alveolar macrophages stimulated by bleomycin-induced injury secrete large quantities of biologically active TGF-beta 1 when explanted into tissue culture. However, alveolar macrophages from normal saline-treated rats secrete small quantities of biologically inactive TGF-beta. In contrast, splenic macrophages secrete large quantities of inactive TGF-beta and are unaffected by the intratracheal bleomycin treatment. High doses of the corticosteroid methylprednisolone given intramuscularly before and concomitantly with bleomycin administration prevented the influx of alveolar macrophages into the lungs, diminishing both the number of macrophages present in the alveoli and the total lung content of TGF-beta. However, the rate of secretion of TGF-beta by alveolar macrophages recovered from the alveoli was unchanged after corticosteroid treatment. When activated alveolar macrophages were cultured in the presence of several concentrations of dexamethasone that completely suppressed IL-1 secretion, little effect on TGF-beta secretion was observed. The findings in this study demonstrate that during bleomycin-induced injury, alveolar macrophages not only secrete large quantities of active TGF-beta 1, but are a predominant source of the enhanced TGF-beta response seen in this model. Furthermore, the alveolar macrophage secretion of TGF-beta is not inhibited by the presence of high concentrations of corticosteroids.

Animals↗
PubMed1986

Analysis of bronchoalveolar lavage fluid from bleomycin-induced pulmonary fibrosis in hamsters.

The purpose of this study was to analyze the cellular and noncellular components of bronchoalveolar lavage fluid (BALF) at varying times during the development of pulmonary fibrosis induced by bleomycin. Hamsters were killed and lavaged in situ following the administration of a single intratracheal injection of 1 unit of bleomycin or an equivalent volume of sterile isotonic saline. The results show that the total cell counts in the BALF of bleomycin-treated hamsters, as compared with controls, were increased 7.7, 4.4, 2.4, 1.6, and 1.9-fold at 2, 4, 7, 14, and 21 days after treatment, respectively. The predominant cell types in the BALF of control animals were macrophages which constituted 84% of the total cells, followed by lymphocytes, 11%. The predominant cell types in the BALF of bleomycin-treated animals were polymorphonuclear leukocytes (PMN) which constituted 65% at two days and approximately 50% of the total at 4, 7, and 14 days; at 21 days macrophages were the predominant cell type constituting 50%, followed by lymphocytes at 30%. However, the total number of lymphocytes was not increased at 21 days compared to previous times. The noncellular protein content of BALF from bleomycin-treated hamsters, an index of pulmonary vascular permeability, was increased to 224, 559, 637, and 270% of control (2.7 mg/lung) at 2, 4, 7, and 14 days after treatment, respectively, and returned to control levels at 21 days. The acid phosphatase activity in the supernatant of BALF of bleomycin-treated animals was significantly increased to 181, 181, 199, 176, and 125% of control (258 units/lung) at 2, 4, 7, 14, and 21 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1982

Clinical pharmacology of bleomycin and cisplatin.

Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs, with activity for head and neck tumors, that were introduced into clinical use in the past ten years. Bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin possesses significant activity against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (terminal phase half-life = 2-4 h), although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (terminal phase half-life = 40-50 h). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous are pyretic; severe nausea and vomiting represents the major acute toxicity of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use, and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.

Bleomycin↗
PubMed2001

Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats.

Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance such as pulmonary fibrosis. This study examines the effect of N-acetylcysteine (NAC) on bleomycin-induced lung fibrosis in rats. NAC (3 mmol x kg(-1); oral) was given daily from 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) or saline, until 14 days postinstillation. NAC partially decreased the augmented collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,354+/-386 and 3,416+/-326 microg x lung(-1) in vehicle-treated and NAC-treated rats, respectively; p < 0.05). The histological assessment using a semiquantitative score showed less collagen deposition and inflammatory cells in NAC-treated rats compared to those receiving bleomycin alone. NAC failed to inhibit the bleomycin-induced increases in lung wet weight and in cell counts and protein levels of bronchoalveolar lavage fluid, but significantly increased total glutathione and taurine levels in bronchoalveolar lavage fluid. These results indicate that oral N-acetylcysteine improves the pulmonary antioxidant protection and may be useful in reducing lung damage produced by bleomycin.

Acetylcysteine↗
PubMed2001

Genetic deficiency of alpha1-PI in mice influences lung responses to bleomycin.

It has recently been suggested that proteinase inhibitors modulate the fibrotic response in the lung. This study investigated the development of bleomycin-induced pulmonary changes in pallid mice, deficient in serum alpha1-proteinase inhibitor, and with a lower elastase inhibitory capacity, and in congenic C57Bl/6J mice. Male pallid and C57Bl/6J mice received a single intratracheal instillation of either saline or bleomycin. The investigation was carried out by means of biochemical, morphological and morphometrical methods. In both strains, 21 and 72 h after bleomycin, the lungs showed foci of inflammatory cell infiltration associated with emphysema. Fibrosis developed with time after bleomycin. At 14 days fibrosis affected 23.46+/-9.48% (mean +/- SD) and 40.62+/-13.34% (p < 0.01) of the lungs of C57Bl/6J and pallid mice, respectively. Emphysema affected 3.68+/-3.11% and 12.57+/-4.13% (p<0.01) of lung in C57Bl/6J and pallid mice, respectively. In C57Bl/6J mice bleomycin increased lung hydroxyproline content by 34% and desmosine content by 44% (p < 0.01 for both). In pallid mice these increases were only 21% (p < 0.01) and 6% which may reflect parenchymal loss. Thus, the lung destructive response (emphysema) and the subsequent proliferative reaction (fibrosis) to bleomycin are potentiated in alpha1-proteinase inhibitor deficiency.

Animals↗
PubMed1999

ICAM-1 mediates lung leukocyte recruitment but not pulmonary fibrosis in a murine model of bleomycin-induced lung injury.

Bleomycin-induced lung injury has been extensively used as a model of interstitial pneumonia and pulmonary fibrosis. Intercellular adhesion molecule (ICAM)-1 is a ligand for lymphocyte function-associated antigen (LFA)-1alpha and has been shown to be required for leukocyte migration into inflamed areas. The purpose of this report was to investigate the role of the ICAM-1/LFA-1alpha pathway in a murine model of bleomycin-induced lung injury. Animals received 75 mg x kg(-1) bleomycin (BLM) i.v. followed by treatment with phosphate-buffered saline (BLM group), anti-ICAM-1 and LFA-1alpha monoclonal antibodies (mAb) (BLM+mAb group). Inflammatory cell counts of bronchoalveolar lavage (BAL) fluid, hydroxyproline content and histological findings were compared between these groups. In the BLM group, significant increases in total cell count, macrophage count and neutrophil count of BAL fluid were observed on days 7 and 14. In the BLM+mAb group, bleomycin-induced accumulation of neutrophils was significantly reduced on days 7 and 14 (p<0.01). However, the administration of mAb to ICAM-1 and LFA-1alpha did not decrease the lung hydroxyproline content or the histopathological fibrosis grading score, indicating that the antagonism of ICAM-I and LFA-1alpha did not attenuate bleomycin-induced pulmonary fibrosis. This study suggests that the intercellular adhesion molecule-1/lymphocyte function-associated antigen-1alpha pathway mediates the accumulation of inflammatory cells in the injured lung caused by bleomycin; however, other mechanisms are important for the subsequent development of pulmonary fibrosis.

Animals↗
PubMed2005

The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis.

BACKGROUND: Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47phox -/- (KO) mice, deficient for ROS production through the NADPH-oxidase pathway. METHODS: Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL) or lung removal. RESULTS: BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47phox -/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid) was strikingly greater in KO than wild-type (WT) mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. CONCLUSIONS: These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis.

Animals↗
PubMed2006

Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury.

Leukotrienes are increased locally in idiopathic pulmonary fibrosis. Furthermore, a role for these arachidonic acid metabolites has been thoroughly characterized in the animal bleomycin model of lung fibrosis by using different gene knock-out settings. We investigated the efficacy of pharmacological inhibition of leukotrienes activity in the development of bleomycin-induced lung injury by comparing the responses in wild-type mice with mice treated with zileuton, a 5-lipoxygenase inhibitor and MK-571, a cys-leukotrienes receptor antagonist. Mice were subjected to intra-tracheal administration of bleomycin or saline and were assigned to receive either MK-571 at 1 mg/Kg or zileuton at 50 mg/Kg daily. One week after bleomycin administration, BAL cell counts, lung histology with van Gieson for collagen staining and immunohistochemical analysis for myeloperoxidase, IL-1 and TNF-alpha were performed. Following bleomycin administration both MK-571 and zileuton treated mice exhibited a reduced degree of lung damage and inflammation when compared to WT mice as shown by the reduction of:(i) loss of body weight, (ii) mortality rate, (iii) lung infiltration by neutrophils (myeloperoxidase activity, BAL total and differential cell counts), (iv) lung edema, (v) histological evidence of lung injury and collagen deposition, (vi) lung myeloperoxidase, IL-1 and TNF-alpha staining. This is the first study showing that the pharmacological inhibition of leukotrienes activity attenuates bleomycin-induced lung injury in mice. Given our results as well as those coming from genetic studies, it might be considered meaningful to trial this drug class in the treatment of pulmonary fibrosis, a disease that still represents a major challenge to medical treatment.

Animals↗
PubMed2006

EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-beta signaling in lung fibroblasts.

BACKGROUND: Fourteen-membered ring macrolides have been effective in reducing chronic airway inflammation and also preventing lung injury and fibrosis in bleomycin-challenged mice via anti-inflammatory effects. EM703 is a new derivative of erythromycin (EM) without the bactericidal effects. We investigated the anti-inflammatory and antifibrotic effects of EM703 in an experimental model of bleomycin-induced lung injury and subsequent fibrosis in mice. METHODS: Seven-week-old male ICR mice were used. All experiments used eight mice/group, unless otherwise noted in the figure legends. Bleomycin was administered intravenously to the mice on day 0. EM703 was orally administered daily to mice. All groups were examined for cell populations in the bronchoalveolar lavage (BAL) fluid and for induction of messenger RNA (mRNA) of Smad3 and Smad4 in the lung tissues by reverse transcriptase (RT)-polymerase chainreaction (PCR) on day 7. Fibroblastic foci were assessed histologically, and the hydroxyproline content was chemically determined in the lung tissues on day 28. We performed assay of proliferation and soluble collagen production, and examined the induction of mRNA of Smad3 and Smad4 by RT-PCR in murine lung fibroblast cell line MLg2908. We also examined Smad3, Smad4 and phosphorylated Smad2/3 (p-Smad2/3) protein assay by western blotting in MLg2908. RESULTS: Bleomycin-induced lung fibrosis, and the infiltration of macrophages and neutrophils into the airspace were inhibited by EM703. The expression of Smad3 and Smad4 mRNA was clearly attenuated by bleomycin, but was recovered by EM703. EM703 also inhibited fibroblast proliferation and the collagen production in lung fibroblasts induced by Transforming growth factor-beta (TGF-beta). The expression of Smad3 and Smad4 mRNA in murine lung fibroblasts disappeared due to TGF-beta, but was recovered by EM703. EM703 inhibited the expression of p-Smad2/3 and Smad4 protein in murine lung fibroblasts induced by TGF-beta. CONCLUSION: These findings suggest that EM703 improves bleomycin-induced pulmonary fibrosis in mice by actions of anti-inflammation and regulation of TGF-beta signaling in lung fibroblasts.

Animals↗
PubMed2005

The need for routine bleomycin test dosing in the 21st century.

OBJECTIVE: To review the clinical evidence for routine use of bleomycin test dosing. DATA SOURCES: English-language review articles, references from retrieved articles, case reports, and clinical trials were identified from a MEDLINE literature search (1966-July 2005). Key search terms included bleomycin, test dose, anaphylactic reactions, and hypersensitivity. Information from an unpublished E-mail survey, the manufacturer, and the Internet was also used. DATA SYNTHESIS: Early clinical trials and isolated case reports suggest that bleomycin-induced acute hypersensitivity reactions occur in 1% of patients with lymphoma and <0.5% of those with solid tumors. The reactions are mainly characterized by high-grade fever, chills, hypotension, and in a few cases, cardiovascular collapse, which can lead to death. The exact mechanism of these reactions is unclear, but is thought to be related to the release of endogenous pyrogens from the host cells. Evidence does not suggest any correlation between doses and the onset or severity of the reactions. Supportive care, including hydration, steroids, antipyretics, and antihistamines, may resolve the symptoms. However, it may not completely prevent recurrences. CONCLUSIONS: The incidence of acute hypersensitivity or hyperpyrexic reactions associated with bleomycin is very low, but the reaction is potentially fatal. Clinicians should monitor their patients for any signs and symptoms of acute hyperpyrexic reactions during bleomycin administration. Since the onset of the reactions can occur with any dose of bleomycin and at any time, routine test dosing does not seem to predict when drug reactions may occur.

Antibiotics, Antineoplastic↗