Beneficial effects of a novel anti-hypoxemic agent, TEI-7322, on bleomycin-induced experimental hypoxemia in rats

Horiuchi, Hideki; Uejima, Yoji; Sakuma, Yasuji; Kadota, Takashi; Okada, Naotaka; Taniguchi, Kaoru; Takenouchi, Kazuya; Yamanaka, Yoshihiro; Uno, Hiroshi; Komoriya, Keiji

doi:10.1016/0014-2999(95)00468-7

Cited by 3 publications

(4 citation statements)

References 24 publications

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“…Likewise, as with previous reports, bleomycin-treated C57BL/6 mice developed pulmonary oedema, deduced from the significant increase in wet lung weights following bleomycin treatment, compared to vehicle control mice [29,30]. Furthermore, albeit not a significant difference, the observed reduction in body weight of bleomycin-treated C57BL/6 mice was likely to be the outcome of the brisk inflammatory response occurring in the lung as previously reported [29,31,32,33,34,35]. …”

Section: Discussionsupporting

confidence: 65%

Assessment of Respiratory Physiology of C57BL/6 Mice following Bleomycin Administration Using Barometric Plethysmography

et al. 2011

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Background: Assessment of deterioration of lung function in animal models of respiratory disease traditionally relies upon quantitating biochemical markers. Plethysmography is a technique for measuring lung function that includes invasive and non-invasive methodologies. Objectives: This study used whole-body barometric plethysmography to characterize change(s) in respiratory physiology of C57BL/6 mice following bleomycin administration. Methods: Cohorts of animals were culled at 3, 7, 14 and 28 days to semi-quantitatively score the lung for fibrosis, and quantitate levels of hydroxyproline in the lung. We have described in detail the response of C57BL/6 mice to bleomycin. Results: Bleomycin-treated mice had reduced minute volume (p < 0.05) and an increased total breathing cycle time (p < 0.0001), which consisted of a shortened inspiration time (p < 0.01) and an extended expiration time (p < 0.0001). Conclusions: We have demonstrated that plethysmography can be a primary indicator of the development of respiratory disease in the mouse and would thus be suitable in assessing potential therapies since any truly effective treatment should elicit restoration of respiratory parameters in addition to improving traditional biochemical and histological indices of lung function.

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Section: Discussionsupporting

confidence: 65%

Assessment of Respiratory Physiology of C57BL/6 Mice following Bleomycin Administration Using Barometric Plethysmography

et al. 2011

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“…The significant increase in AaDO 2 indicates an impairment of pulmonary gas exchange, such as ventilation-perfusion inequality and/or diffusion impairment. It has been suggested that the histological changes such as interstitial pneumonitis and thickening of alveolar walls in bleomycin-administered lungs may cause an increase in pulmonary elastic recoil which results in diffusion disturbance and pulmonary vasoconstriction reduction [10]. Furthermore, the increase in pulmonary elastic recoil might induce thickening of arterial walls, finally resulting in hypertrophy of the right ventricle [30].…”

Section: Discussionmentioning

confidence: 99%

“…Key words: bleomycin, catheter, diffusion disturbance, erythrocyte count, ventilationperfusion imbalance the precise mechanisms involved in the induction of this disease have not been clarified completely. In rodents, a single intratracheal administration under anesthesia is frequently used for preparing an animal model [7,10,23,26,32], but the extent and severity of pulmonary damage caused by bleomycin varies considerably depending on the attainability of the drug solution [16]. Furthermore, anesthesia itself causes respiratory and…”

Section: Introductionmentioning

confidence: 99%

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

et al. 2004

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Abstract:In order to ensure a widespread distribution in the lung and to avoid the effect of anesthesia, bleomycin at a total dose of 4.5 or 6.0 mg/kg was administered in four divided doses (0.5 ml/kg/time) at intervals of 2 h to male rats via a catheter (tracheotomy tube) without anesthesia. In comparison to vehicle (saline) controls, bleomycin-treated rats showed a significant suppression of body weight gain that was observed transiently at 4.5 mg/kg and continuously (throughout the 3-week observation period) at 6.0 mg/kg. Histopathologically, interstitial pneumonitis, thickening of alveolar walls, thickening of pulmonary arterial walls, foamy cells in alveoli, and hemorrhage were observed in both 4.5 and 6 mg/kg groups, and also emphysema in the 6 mg/kg group. Both groups exhibited a significant decrease in the partial pressure of arterial oxygen (PaO 2 ) and a significant increase in alveolar-arterial oxygen tension difference (AaDO 2 ), and a significant increase in erythrocyte count was observed in the 6 mg/kg group. Furthermore, both treated groups showed a significant increase in the ratio of the right ventricular weight versus left ventricle plus septum weights. The significant increase in erythrocyte count might have been caused by diffusion disturbance and ventilation-perfusion imbalance due to the pulmonary damage. These findings suggest that the present experimental method will be useful for clarification of the pulmonary damage induced by bleomycin in rats. Key words: bleomycin, catheter, diffusion disturbance, erythrocyte count, ventilationperfusion imbalance the precise mechanisms involved in the induction of this disease have not been clarified completely. In rodents, a single intratracheal administration under anesthesia is frequently used for preparing an animal model [7,10,23,26,32], but the extent and severity of pulmonary damage caused by bleomycin varies considerably depending on the attainability of the drug solution [16]. Furthermore, anesthesia itself causes respiratory and

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“…Our results indicate that bleomycin indirectly activates extra-mitochondrial anaerobic glycolysis reflected by the increase in lung tissue lactate. The reason for this effect is unclear but it may be related to hypoxic areas within bleomycin-induced fibrotic lesions, as previously described [ 37 , 38 ]. Further, bleomycin might impair mitochondrial functions by facilitating the formation of oxygen radicals.…”

Section: Discussionmentioning

confidence: 91%

Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

et al. 2015

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Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.

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Beneficial effects of a novel anti-hypoxemic agent, TEI-7322, on bleomycin-induced experimental hypoxemia in rats

Cited by 3 publications

References 24 publications

Assessment of Respiratory Physiology of C57BL/6 Mice following Bleomycin Administration Using Barometric Plethysmography

Assessment of Respiratory Physiology of C57BL/6 Mice following Bleomycin Administration Using Barometric Plethysmography

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

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