Rodent Model of Bleomycin Fibrosis

Thioredoxin is a multifunctional redox (reduction/oxidation)-active protein that scavenges oxygen species by itself or in conjunction with thioredoxin-dependent peroxiredoxin. Hoshino and coworkers studied the effects of thioredoxin in two mouse models of interstitial lung disease: the conventional model of bleomycin-induced injury, and a new model of lethal lung injury induced by the daily administration of the proinflammatory cytokines, interleukin-18 and interleukin-2. In the bleomycin model, administration of thioredoxin decreased cellular infiltrates and fibrosis in both wild-type and thioredoxin-transgenic mice. In the model caused by administration of proinflammatory cytokines, administration of thioredoxin suppressed the interstitial cell infiltrates, suppressed tissue damage, and prevented death; suppression was evident also in thioredoxin-transgenic mice. The authors conclude that thioredoxin modulates pulmonary inflammation and prevents lung injury caused by administration of either bleomycin or proinflammatory cytokines. An editorial commentary by Crapo accompanies this article.

In rabbits subjected to bleomycin-induced lung injury, Gunther and coworkers investigated the role of alveolar fibrin formation in the resulting lung fibrosis. Four weeks after administration of the aerosol of bleomycin, animals exhibited typical features of pulmonary fibrosis. Delivery of either heparin or urokinase-type plasminogen activator to the bronchoalveolar space normalized lung compliance, suppressed the accumulation of collagen and hydroxylproline, and virtually abrogated the features of fibrosis on computer tomography and histology. The most prominent effects were seen with early administration of heparin or late administration of urokinase-type plasminogen activator. Bleeding complications were not observed. The authors conclude that alveolar fibrin generation plays an important role in the development of lung fibrosis after administration of bleomycin to rabbits. An editorial commentary by Idell accompanies this article.

${gamma}$ -Glutamyl transpeptidase is a key enzyme in glutathione and cysteine metabolism. Because cysteine deficiency may impair extracellular matrix synthesis, Pardo and coworkers asked, "Would mice deficient in ${gamma}$ -glutamyl transpeptidase (GGT^-/-) develop less fibrosis after exposure to bleomycin than would wild-type (GGT^+/+) mice"? At 72 hours after exposure to bleomycin, the null mice displayed a near absence of neutrophils in lung tissue and a less pronounced rise in matrix metalloproteinase-9 than did the wild-type mice; inflammation in null mice consisted mainly of lymphocytes and macrophages. At 1 month, an index of lung fibrosis was 74% less in null mice than in wild-type mice. Lung collagen almost doubled after bleomycin in wild-type mice, but not in the null mice. Control lungs in null mice showed a 45% decrease in cysteine and a 31% decrease in glutathione. Levels of cysteine and glutathione decreased at 72 hours after bleomycin in both null and wild-type mice, but returned to control values after 1 month. Supplementation with N-acetylcysteine partly ameliorated the effects of ${gamma}$ -glutamyl transpeptidase deficiency. The authors conclude 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.

Platelet-derived growth factor is involved in the pathogenesis of lung fibrosis. Shimizu and coworkers investigated the effect of a natural anticoagulant, activated protein C, on platelet-derived growth factor expression in human cell lines and in an in vivo model of lung fibrosis. Activated protein C inhibited the secretion and expression of platelet-derived growth factor in human lung cell lines, primary bronchial epithelial cells, and macrophages. In vivo studies revealed that the endothelial activated protein C receptor was expressed by lung epithelial cells and macrophages; the receptor and proteolytic activity of the activated protein were implicated in inhibiting the expression of platelet-derived growth factor. In an in vivo model of lung fibrosis (bleomycin injury in mice), intratracheal administration of activated protein C decreased the expression of platelet-derived growth factor and suppressed the development of lung fibrosis. The inhibitory activity of activated protein C was inhibited by the concomitant administration of anti-endothelial activated protein C receptor or anti–platelet-derived growth factor. The authors conclude that activated protein C inhibits the expression of platelet-derived growth factor in the lung and suppresses lung fibrosis caused by bleomycin.

The rate of transferring small molecular solutes across the alveolar–capillary membrane is altered by acute lung damage. Suga and coworkers did magnetic resonance imaging during and after inhalation of an aerosol of gadolinium diethylenetriaminepentaacetic acid in dogs with bleomycin-induced injury. Deposition of the aerosol was decreased heterogeneously at 7 and 40 days after intratracheal instillation of bleomycin. Seven days after intratracheal instillation of bleomycin, the slope of the clearance curve for the aerosol was increased by 47% over baseline and clearance half-time was decreased by 29%. Both measures of clearance had returned to baseline at 40 days after the instillation of bleomycin. The authors conclude that dogs display accelerated clearance of an aerosol of gadolinium diethylenetriaminepentaacetic acid during the acute exudative phase of bleomycin-induced injury and recovery occurs during the chronic fibrotic phase.

Citations 1-7 of 7 total displayed.

The Matrix Unloaded: Aerosolized Heparin or Urokinase for Pulmonary Fibrosis

Steven Idell
Am. J. Respir. Crit. Care Med. 168: 1268-1269. [Full text]

Prevention of Bleomycin-induced Lung Fibrosis by Aerosolization of Heparin or Urokinase in Rabbits

Andreas Günther, Norbert Lübke, Monika Ermert, Ralph T. Schermuly, Norbert Weissmann, Andreas Breithecker, Philipp Markart, Clemens Ruppert, Karin Quanz, Leander Ermert, Friedrich Grimminger, and Werner Seeger
Am. J. Respir. Crit. Care Med. 168: 1358-1365. [Abstract] [Full text]

Redox Active Agents in Inflammatory Lung Injury

James D. Crapo
Am. J. Respir. Crit. Care Med. 168: 1027-1028. [Full text]

Redox-active Protein Thioredoxin Prevents Proinflammatory Cytokine- or Bleomycin-induced Lung Injury

Tomoaki Hoshino, Hajime Nakamura, Masaki Okamoto, Seiya Kato, Shinichi Araya, Keiko Nomiyama, Kotaro Oizumi, Howard A. Young, Hisamichi Aizawa, and Junji Yodoi
Am. J. Respir. Crit. Care Med. 168: 1075 -1083. First published online as doi:10.1164/rccm.200209-982OC [Abstract] [Full text]

Altered Clearance of Gadolinium Diethylenetriaminepentaacetic Acid Aerosol from Bleomycin-injured Dog Lungs: Initial Observations

Kazuyoshi Suga, Yue Yuan, Nobuhiko Ogasawara, Toshinobu Tsukuda, and Naofumi Matsunaga
Am. J. Respir. Crit. Care Med. 167: 1704 -1710. First published online as doi:10.1164/rccm.200207-665OC [Abstract] [Full text]

Activated Protein C Inhibits the Expression of Platelet-derived Growth Factor in the Lung

Shino Shimizu, Esteban C. Gabazza, Osamu Taguchi, Hiroki Yasui, Yukiko Taguchi, Tatsuya Hayashi, Masaru Ido, Takeshi Shimizu, Tomohiro Nakagaki, Hiroshi Kobayashi, Kenji Fukudome, Naoko Tsuneyoshi, Corina N. D'Alessandro-Gabazza, Masahiko Izumizaki, Michiko Iwase, Ikuo Homma, Yukihiko Adachi, and Koji Suzuki
Am. J. Respir. Crit. Care Med. 167: 1416-1426. [Abstract] [Full text]

Bleomycin-induced Pulmonary Fibrosis Is Attenuated in ${gamma}$ -Glutamyl Transpeptidase–Deficient Mice

Annie Pardo, Víctor Ruiz, José Luis Arreola, Remedios Ramírez, José Cisneros-Lira, Miguel Gaxiola, Roberto Barrios, Subbarao V. Kala, Michael W. Lieberman, and Moisés Selman
Am. J. Respir. Crit. Care Med. 167: 925 -932. First published online as doi:10.1164/rccm.200209-1007OC [Abstract] [Full text]

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