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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of alveolar macrophage (AM)-derived secretory products in fibroblast stimulation after the instillation of long and short asbestos to rat lungs is now investigated. A pure sample of 1 mg long crocidolite (greater than 2.5 mu) induced pulmonary fibrosis in 8 weeks, but secretions of lavaged AM from these lungs did not enhance growth or collagen synthesis in cultured rat lung fibroblasts. In contrast, the same dose of short fibers did not produce pulmonary fibrosis, although AM lavaged from these lungs were increased in number, had more phagocytized fibers, and when incubated, secreted factors that stimulated fibroblasts in culture. When normal AM were exposed to these fiber samples for 24 hours in vitro, greater phagocytosis of particles occurred and each asbestos fiber sample induced secretion of an AM-derived growth factor for cultured fibroblasts. The results indicate that both long and short fibers are capable of inducing AM to secrete fibrogenic factors in vitro, but in vivo, cytokine secretion by AM into the alveolar spaces in response to short fibers is not associated with stimulation of the interstitial fibroblast. In contrast, pulmonary fibrosis after long fiber administration appears unrelated to an AM secretion and is probably caused by fiber penetration into the peribronchiolar tissue, where interstitial macrophage activation may occur over several weeks.
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PMID:Pulmonary reaction to long and short asbestos fibers is independent of fibroblast growth factor production by alveolar macrophages. 239 32

Endotracheal bleomycin administration in rats and other animal species causes rapid development of pulmonary fibrosis, characterized by increased lung collagen synthesis and deposition. To clarify the mechanism, lung fibroblasts from bleomycin-treated rats (BRF) were isolated and maintained in tissue culture. They were then compared with those from normal untreated control animals, with respect to several key parameters of collagen metabolism. BRF synthesized collagen at a rate 35-82% above normal rat lung fibroblasts (NRF). This difference did not appear to be due to the selection of a clone by the subculture process. Furthermore, analysis of newly synthesized collagen type composition, revealed a significantly lower ratio of type III to type I collagen. Noncollagenous protein synthesis, however, was not significantly different from normal. Collagenase production and growth rate were also unaffected. BRF, however, was morphologically indistinguishable from NRF, even at the ultrastructural level. Upon further bleomycin (1 microgram/ml) exposure in vitro, BRF could be further stimulated to synthesize collagen at 82% above the rate for untreated BRF. This is comparable to the 90% increase in NRF treated in vitro (compared with untreated NRF). These results would favor the conclusion that bleomycin induces pulmonary fibrosis, by causing directly and/or indirectly lung fibroblasts (or a certain line of lung fibroblasts) to synthesize collagen at a higher rate without any associated increase in growth rate. The data, however, do not rule out the possibility that the fibroblast isolation procedure has selected for a certain population of fibroblasts that may not be typical of the in vivo situation.
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PMID:Rat lung fibroblast collagen metabolism in bleomycin-induced pulmonary fibrosis. 241 Apr 57

Bleomycin damages cellular DNA and is a potent inducer of pulmonary fibrosis. It has been shown to act through a superoxide-mediated mechanism. We are interested in determining the biochemical mechanisms involved in fibrosis and in this preliminary study we have examined the temporal relationship between early biochemical events associated with DNA damage and fibrosis, in lungs of hamsters after administration of 0.75 unit of bleomycin. The activities of poly(ADP-ribose) synthetase, an enzyme associated with DNA repair, inducible superoxide dismutase (SOD) and prolyl hydroxylase as well as the tissue levels of NAD+ and hydroxyproline in the lung were determined. All three enzyme activities expressed as per milligram DNA or per lung, increased upon bleomycin treatment over the saline-administered controls. Lung poly(ADP-ribose) synthetase activity which is sensitive to DNA breaks, increased first (24% over control in 1 day, P less than 0.0001), attained the maximum value on the 5th day (952% over control, P less than 0.0001), and started to decline thereafter and approached near the control value on 14th day. Bleomycin treatment induced a rapid change in the level of lung NAD+. After 1 day the level of NAD+ was reduced by 42% compared to the control (P less than 0.001), further declined to 65% (P less than 0.001) on the 3rd day, and stayed at that level until the 7th day. On the 14th day, however, the NAD+ level was still lower (29%, P less than 0.05) but approaching the value in the control animals. The activity of prolyl hydroxylase showed significant increase on the 3rd day (50% over control, P less than 0.0001) after bleomycin administration. The enzyme activity continued to increase until the end of the experiment (490% of control, P less than 0.0001, on Day 14). The content of undialyzable hydroxyproline, a marker for collagen, was also increased significantly in the lung tissue on the 3rd day (30% over control, P less than 0.05), continued to increase and reached the highest level on the 14th day (71% over control, P less than 0.001). A significant increase in the activity of SOD (19% over control, P less than 0.001) was seen on the 5th day which continued to increase and attained the highest value on Day 14 (115% over control, P less than 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Poly(ADP-ribose) synthetase activity during bleomycin-induced lung fibrosis in hamsters. 241 86

Bleomycin is a commonly used antineoplastic agent which produces dose- and time-dependent pneumonitis and fibrosis in humans. The mechanism of bleomycin-induced lung injury is uncertain. However, current data shows that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. We therefore investigated whether intraperitoneal (i.p.) injection of endotoxin, a protectant for hyperoxia, could modulate the biochemical and morphological estimates of bleomycin-induced lung fibrosis in rats. However, pretreatment with multiple i.p. injections of endotoxin, combined with intratracheal bleomycin instillation, resulted in increased lung collagen content compared to bleomycin treatment alone and controls. Furthermore, morphological estimates of the severity of lung lesions present in the endotoxin-bleomycin treatment group were increased when compared with saline and endotoxin control lung lesions. These data indicate, in the current study design, that endotoxin did not reduce, but instead increased the severity of bleomycin-induced pulmonary fibrosis in rats. The mechanism for this increase in fibrosis may be the result of pre-existing endotoxin-induced cell injury.
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PMID:The effect of endotoxin on bleomycin-induced lung fibrosis in the rat. 241 66

The concomitant treatment of rats with bleomycin and hyperoxia results in synergistic development of pulmonary injury. We exposed rats to 70% oxygen for 72 hr following an intratracheal instillation of bleomycin (0.2 U/kg body wt). Animals were killed 15, 30, 60 and 90 days after treatment for hydroxyproline, cell kinetics, and histopathologic analysis. A 16% increase in hydroxyproline over controls was seen 15 days after treatment which was manifested by the proliferation phase of diffuse alveolar damage and an increase in cell labeling by tritiated thymidine. Thirty days after treatment the hydroxyproline remained elevated while lung injury appeared to be healing with a residual focal interstitial pneumonitis and a drop in cell labeling. Between 60 and 90 days, there was an additional significant increase in hydroxyproline to 44% over controls. Diffuse interstitial pneumonitis with fibrosis was observed. Cell labeling remained constant between 60 and 90 days. We conclude that the treatment of rats with bleomycin and hyperoxia results in slowly progressive pulmonary fibrosis. The increase in hydroxyproline in the chronic phase was not accompanied by an increase in cell proliferation, and therefore may have resulted from an increase in cellular production of hydroxyproline rather than increased number of cells producing collagen.
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PMID:Progressive pulmonary fibrosis in rats: a biochemical, cell kinetic, and morphologic analysis. 241 89

We have produced experimental diffuse interstitial pulmonary fibrosis in rats with a combination of low and repeated doses of paraquat plus continuous exposure to normobaric 74% O2 in the breathing air for several weeks. Pulmonary fibrosis was evaluated histologically and biochemically, through the determination of total collagen content in the lung. Our procedure is characterized by low initial mortality, the development of extensive distortion of the pulmonary architecture, and the presence of severe and diffuse interstitial fibrosis. The model was compared with bleomycin-induced pulmonary fibrosis in the same rat strain, in which the process is focal and leaves most of the lung unaffected. We conclude that lung damage produced by the combination of low doses of paraquat plus normobaric 74% O2 concentration in the breathing air is an adequate experimental model of diffuse interstitial pulmonary fibrosis as it occurs in many of the human cases of this condition.
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PMID:A new model of diffuse interstitial pulmonary fibrosis in the rat. 241 90

The role of alveolar macrophage activation and release of mediators remains unclear. In this study, this role is examined with respect to the effects of relatively selective inhibitors of arachidonate metabolism on the pathogenesis of pulmonary fibrosis. CBA/J mice were administered bleomycin (0.037 units) endotracheally to induce pulmonary fibrosis. Daily intraperitoneal injections of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) inhibited pulmonary fibrosis in a dose-dependent manner (15-25 mg/kg body weight), as assessed by both lung collagen synthesis and total lung hydroxyproline content. The less specific inhibitor BW755c was also effective at a dose of 25 mg/kg. In contrast, the cyclooxygenase inhibitor, ibuprofen (15 mg/kg), was completely ineffective. Correlated with this antifibrogenic activity of NDGA was the inhibition of several other parameters of bleomycin-induced pulmonary fibrosis. Bleomycin treatment caused a greater than threefold increase in the percentage of alveolar macrophages expressing Ia antigen (from 7.7% +/- 1.07% to 29.9% +/- 4.16% of total recoverable alveolar macrophages). NDGA, but not ibuprofen, inhibited this increase in a dose-dependent manner. Associated with this indication of macrophage stimulation was an increase in spontaneous macrophage production of fibroblast growth factor (MDGF) activity as a result of bleomycin instillation. This increase was also inhibited by NDGA treatment. In contrast, bleomycin treatment caused a reduction in alveolar macrophage interleukin-1 (IL-1) production, and NDGA treatment did not alter this reduction, which suggests that MDGF is separate from IL-1 in this case, and that MDGF played a more dominant role, at least in this model of pulmonary fibrosis. This antifibrogenic activity of NDGA was accomplished without any reduction in spontaneous macrophage prostaglandin (PG)E2 production, which suggests the selectivity (versus cyclooxygenase pathway) of NDGA inhibition and the relative lack of importance of macrophage-derived PGE2 in modulating fibrogenesis in this model. The results of this study have thus demonstrated the importance of alveolar macrophage stimulation and increased production of MDGF in the pathogenesis of bleomycin-induced pulmonary fibrosis. The data also suggest that both macrophage parameters are subject to regulation by arachidonate metabolites.
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PMID:Inhibition of bleomycin-induced pulmonary fibrosis by nordihydroguaiaretic acid. The role of alveolar macrophage activation and mediator production. 242 52

A single intratracheal injection of 50 mg crystalline silica (quartz) into rats produces silicosis. This animal model may be used to study collagen metabolism during the early, middle, and late phases of lung injury, corresponding respectively to the stages of lung injury, development of discrete granulomas, and development of mature silicotic nodules. The early phase is characterized by a rapid increase in the rate of synthesis of lung collagen (within one week of instillation) and increased deposition of excess lung collagen (significant increases within two weeks of instillation). Later phases are characterized by a continuing increase in deposition of excess lung collagen for at least one year after instillation. Silica-induced fibrosis is unique among all the animal models (and in most human fibrotic diseases) thus far examined, in that the excess collagen deposited in the lung contains normal ratios of the two major collagen types of the lung: types I and III. This collagen is nonetheless biochemically different from normal lung collagen. There are reproducible and characteristic differences in the intermolecular cross-links of the collagen in lungs from rats injected with silica. Within one month of silica instillation (the earliest time point examined thus far), an increased hydroxylysine content of collagen can be appreciated. The reducible dysfunctional cross-links are also more likely to be derived from hydroxylysine (i.e. the ratio of dihydroxylated to monohydroxylated cross-links increases). Within four months of silica instillation (and increasingly thereafter), increased amounts of the mature trifunctional cross-link hydroxypyridinium (derived from three residues of hydroxylysine) can also be appreciated, seemingly paralleling the evolution of mature silicotic nodules in these lungs. These changes in cross-linking of lung collagen seem to be common to all the animal models of pulmonary fibrosis examined, and are also consistent with changes occurring in human fibrotic lungs. Preliminary observations suggest that the locus of cross-linking remains the same: hydroxylysine replaces lysine in the primary structure of a specific collagen alpha chain to form the altered cross-links. Thus, there may be molecular markers for the collagen of fibrosis in diseased lungs.
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PMID:Effects of silica on lung collagen. 242 84

Previous studies have shown that bleomycin-induced pulmonary fibrosis is accompanied by elevated levels of calcium and calmodulin, which are important in the regulation of many biologic processes. The authors have further extended these observations and assessed the effect of a calmodulin inhibitor, trifluoperazine, on bleomycin-induced lung damage with biochemical, morphometric, and bronchoalveolar lavage techniques. The cumulative mortality due to bleomycin was not significantly reduced in animals receiving trifluoperazine. Trifluoperazine had no apparent effect on lung levels of collagen and DNA elevated by bleomycin. However, morphometric studies showed that the volume density of the lesion, the volume of amorphous material and interstitial inflammation, and the number of monocytes within lesions were less in the lungs of bleomycin-treated hamsters receiving trifluoperazine daily. When compared with hamsters treated with bleomycin alone, animals treated with both bleomycin and trifluoperazine had significantly fewer lymphocytes in their bronchoalveolar lavage fluid. The data suggest that trifluoperazine reduced the acute inflammation which accompanies bleomycin pneumotoxicity but did not affect the subsequent development of pulmonary fibrosis. It has been postulated that the observed antiinflammatory action of trifluoperazine may be due to inhibition of calmodulin-dependent leukocyte functions.
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PMID:Effects of a calmodulin inhibitor on bleomycin-induced lung inflammation in hamsters. Biochemical, morphometric, and bronchoalveolar lavage data. 242 53

Lung fibrosis is a process in which collagen is laid down and the delicate capillary-alveolar relationship is disturbed. The architectural changes which occur in the capillaries, a main element of the oxygen transferring unit, are difficult to illustrate without a three-dimensional tool, such as scanning electron microscopy. Therefore, a scanning electron microscopic study was undertaken to show the capillary changes of lung fibrosis. Fibrosis was induced in rats by intratracheal instillation of bleomycin. After 30 days the rats were sacrificed, and the vascular tree of the lung was cast with methacrylate. The fibrosis was patchy. The intercapillary space became wider; and some capillaries had large, irregular dilatations. Occasionally giant capillaries (up to 19 mu in diameter) were noted. The pleural and alveolar capillary diameters increased (P less than 0.01), and the branching frequency decreased (P = 0.02). The center of the capillary rings, which has been suggested to be the site of contractile interstitial cells, increased in size (P = 0.03). The appearance of irregularly shaped capillaries and an increase in diameter without a change in density of alveolar capillaries, resulting in a loss of surface area and a decrease in branching, are the main scanning electron microscopic findings of the remodeling which occurs in pulmonary capillaries in lung fibrosis. These changes may partially explain the functional derangement of this disease.
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PMID:Capillary remodeling in bleomycin-induced pulmonary fibrosis. 243 Apr 59


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