Genetic deficiency of α1‐PI in mice influences lung responses to bleomycin (original) (raw)
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Genetic deficiency of α1‐PI in mice influences lung responses to bleomycin
The European respiratory journal, 2001
It has recently been suggested that proteinase inhibitors modulate the fibrotic response in the lung. This study investigated the development of bleomycininduced pulmonary changes in pallid mice, deficient in serum a 1-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% (pv0.01) of the lungs of C57Bl/6J and pallid mice, respectively. Emphysema affected 3.68¡3.11% and 12.57¡4.13% (pv0.01) 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% (pv0.01 for both). In pallid mice these increases were only 21% (pv0.01) and 6%, which may reflect parenchymal loss. Thus, the lung destructive response (emphysema) and the subsequent proliferative reaction (fibrosis) to bleomycin are potentiated in a 1-proteinase inhibitor deficiency.
Elastase modifies bleomycin-induced pulmonary fibrosis in mice
Acta histochemica, 2016
Pulmonary fibrosis (PF) is characterized by excessive accumulation of collagen in the lungs. Emphysema is characterized by loss of the extracellular matrix (ECM) and alveolar enlargement. We studied the co-participation of elastase-induced mild emphysema in bleomycin-induced PF in mice by analyzing oxidative stress, inflammation and lung histology. C57BL/6 mice were divided into four groups: control; bleomycin (0.1U/mouse); elastase (using porcine pancreatic elastase (PPE)+bleomycin (3U/mouse 14 days before 0.1U/mouse of bleomycin; PPE+B); elastase (3U/mouse). Mice were humanely sacrificed 7, 14 and 21 days after treatment with bleomycin or vehicle. PF was observed 14 days and 21 days after bleomycin treatment but was observed after 14 days only in the PPE+B group. In the PPE+B group at 21 days, we observed many alveoli and alveolar septa with few PF areas. We also observed marked and progressive increases of collagens 7, 14 and 21 days after bleomycin treatment whereas, in the PPE+...
Background: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period. Methods: Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged-bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model.
Development and time-course of bleomycin-induced pulmonary fibrosis in NMRI mice
DARU, 2007
Bleomycin-induced pulmonary fibrosis is a widely used experimental model for human lung fibrosis. The severity of fibrosis varies among different strains of mice and investigation on different strains and finding the mechanisms of variation is important in understanding the pathogenesis of human lung fibrosis. In the present study, NMRI mice were used to investigate the severity and also time-course of bleomycin-induced pulmonary fibrosis in comparison with C57BL/6 mice. After single dose administration of intratracheal bleomycin, the fibrotic response was studied by biochemical measurement of collagen deposition and semiquantitative analysis of pathological lung changes. NMRI mice developed lung fibrosis from 1 to 4 week after bleomycin instillation, with significant increases in lung collagen content and significant morphological changes (P < 0.05). These findings indicate that NMRI mice might be suitable as an experimental model of bleomycin-induced lung fibrosis.
Bleomycin-induced Pulmonary Fibrosis Is Attenuated in γ-Glutamyl Transpeptidase–Deficient Mice
American Journal of Respiratory and Critical Care Medicine, 2003
To investigate repair mechanisms in bleomycin-induced pulmonary wise, it has been shown that in type 2 epithelial cells, GGT fibrosis, we used mice deficient in ␥-glutamyl transpeptidase (GGT Ϫ/Ϫ), activity is also increased during the inflammatory phase of a key enzyme in glutathione (GSH) and cysteine metabolism. Sevthe bleomycin-induced lung damage in rats (9). On the other enty-two hours after bleomycin (0.03 U/g), GGT Ϫ/Ϫ mice displayed hand, although not all of the functions of the ␥ glutamyl a different inflammatory response to wild-type mice as judged by cycle are known, it has been suggested that one of the major a near absence of neutrophils in lung tissue and bronchoalveolar functions of GGT is the amino acid supply through glutathilavage and a less pronounced rise in matrix metalloproteinase-9. one metabolism, especially cysteine (10). Inflammation in GGT Ϫ/Ϫ mice consisted mainly of lymphocytes and Recently, a GGT-deficient mouse (GGT Ϫ/Ϫ) was genermacrophages. At 1 month, lungs from bleomycin-treated GGT Ϫ/Ϫ ated (11); these animals appear normal at birth but grow and mice exhibited minimal areas of fibrosis compared with wild-type mature slowly and undergo premature death. The GGT Ϫ/Ϫ mice(light microscopy fibrosis index: 510 Ϯ 756 versus 1975 Ϯ 817, mouse phenotype is characterized by glutathionuria and as p Ͻ 0.01). Lung collagen content revealed a significant increase a result became cysteine deficient (11, 12). Feeding N-acetylin bleomycin-treated wild-type (15.1 Ϯ 3.8 versus 8.5 Ϯ 0.7 g cysteine (NAC) to replace lost GSH normalized growth and hydroxy(OH)-proline/mg dry weight, p Ͻ 0.01) but not in GGT Ϫ/Ϫ reversed most of the pathologic effects observed in GGT Ϫ/Ϫ (10.4 Ϯ 1.7 versus 8.8 Ϯ 0.8). Control lungs from GGT Ϫ/Ϫ showed mice. a significant reduction of cysteine (0.03 Ϯ 0.005 versus 0.055 Ϯ Amino acid availability regulates collagen expression, and 0.001, p Ͻ 0.02) and GSH levels (1.24 Ϯ 0.055 versus 1.79 Ϯ 0.065, it has been recently demonstrated that human lung fibroblasts p Ͻ 0.002). These values decreased after 72 hours of bleomycin in exposed to amino acid deprivation reduces type I collagen both GGT Ϫ/Ϫ and wild-type but reached their respective control mRNA expression by decreasing both transcription rate and values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings transcript stability (13). Moreover, in the absence or with low suggest that increased neutrophils and matrix metalloproteinase-9 concentrations of cysteine, fibroblasts produce undetectable during the early inflammatory response and adequate thiol reserves levels of ␣1(I) procollagen protein (14). With these ideas in are key elements in the fibrotic response after bleomycin-induced mind, we designed a study to examine the pulmonary repulmonary injury. sponse to a fibrogenic insult in GGT-deficient mice with the idea of evaluating the roles of decreased levels of lung GSH
Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the mouse
Cancer research, 1996
Based on the range of patient responses to treatment, and on animal studies, it is hypothesized that individual variation in sensitivity to bleomycin-induced pulmonary fibrosis is controlled genetically. A genetic model has been developed by (a) establishing a distinct difference in bleomycin-induced lung damage in two inbred strains of mice [parental generation: C57BL/6J (fibrosis-prone phenotype) and C3Hf/Kam (fibrosis-resistant phenotype)] and (b) characterizing inheritance of the fibrosing phenotype in the F1 (first filial) and F2 (F1 intercross; second filial) generations derived from the parental strains. Male mice received 100 mg/kg and female mice 125 mg/kg of bleomycin via s.c. osmotic minipump. The animals were sacrificed 8 weeks after treatment or when their breathing rate indicated respiratory distress. The percentage of lung with fibrosis for each mouse was quantified with image analysis of a histological section of the left lung. The mean percentage of fibrosis for the...
Experimental mouse model of Bleomycin-induced Pulmonary Fibrosis
2020
Pulmonary fibrosis is a pathologic chronic lung disorder characterized by the deposition of extracellular matrix and damage to lung architecture. Models of pulmonary fibrosis were developed in several animal species. However, murine models are more common due to their low costs, availability and well characterized immune systems. Indeed, these murine models play an important role in understanding the biology of the diseases, deciphering the cellular and molecular mechanisms mediating pulmonary pathobiology and to explore novel therapeutic approaches. Although the majority of these models mimic certain characteristics of human idiopathic pulmonary fibrosis, most of them do not mimic other features especially those related to the progressive and irreversible nature of this disease. The present protocol describes the induction of a pulmonary fibrosis model in mice with bleomycin, which is a risk factor for human lung fibrosis. Specifically, we described the methodology of intratracheal...
International journal of applied research, 2016
Background and objectives: Animal models for human pulmonary fibrosis ideally should reflect detailed characteristics of human disease including inflammation and abnormal epithelial repair with the induction of fibrotic foci. In addition, animal models should be highly reproducible, inexpensive to maintain, easy to perform and accessible. The aim of this study to evaluate the ability of bleomycin to induce pulmonary fibrosis in animal model by different time courses and the best time for its occurrence. Material and methods: This study was conducted in Medical Experimental Research center (MERC) in Mansoura University on C57BL/6 mice. Group (A) C57BL/6 mice (n=6) received 0.25 ml normal saline intraperitoneal twice weekly for 8 weeks and sacrificed two days after last saline dose injection. Group (B) C57BL/6 (n=10) mice received intraperitoneal injection of 0.5mg bleomycin twice weekly for 6 weeks only 6 mice completed the study and sacrificed two days after last bleomycin dose simi...
Lung fibrosis induced by bleomycin: structural changes and overview of recent advances
Scanning …, 1998
This short review addresses the alterations induced by bleomycin in the lung, particularly those related to the induction of fibrosis. Bleomycin is a cytostatic drug commonly employed in the treatment of cancer. As a side effect of its therapeutic use, bleomycin induces in some patients chronic pulmonary inflammation that may progress to fibrosis. Endotracheal instillation of the drug has been adopted as the elective experimental model to reproduce human interstitial fibrosis of the lung in laboratory animals. We recall here the major structural alterations that are triggered by bleomycin in the lung and we overview recent literature regarding cellular and molecular mechanisms that have been identified as participants in the physiopathology of bleomycin-induced lung fibrosis. Recent data obtained with the bleomycin model have offered detailed information on the major molecular mediators of lung fibrosis. This achievement offers the hope that therapeutic strategies based on molecular medicine may have a useful role in improving the treatment of human lung fibrosis in the near future.