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Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis.

ABSTRACT: Single-dose intratracheal bleomycin has been instrumental for understanding fibrotic lung remodeling, but fails to recapitulate several features of idiopathic pulmonary fibrosis (IPF). Since IPF is thought to result from recurrent alveolar injury, we aimed to develop a repetitive bleomycin model that results in lung fibrosis with key characteristics of human disease, including alveolar epithelial cell (AEC) hyperplasia. Wild-type and cell fate reporter mice expressing ?-galactosidase in cells of lung epithelial lineage were given intratracheal bleomycin after intubation, and lungs were harvested 2 wk after a single or eighth biweekly dose. Lungs were evaluated for fibrosis and collagen content. Bronchoalveolar lavage (BAL) was performed for cell counts. TUNEL staining and immunohistochemistry were performed for pro-surfactant protein C (pro-SP-C), Clara cell 10 (CC-10), ?-galactosidase, S100A4, and ?-smooth muscle actin. Lungs from repetitive bleomycin mice had marked fibrosis with prominent AEC hyperplasia, similar to usual interstitial pneumonia (UIP). Compared with single dosing, repetitive bleomycin mice had greater fibrosis by scoring, morphometry, and collagen content; increased TUNEL+ AECs; and reduced inflammatory cells in BAL. Sixty-four percent of pro-SP-C+ cells in areas of fibrosis expressed CC-10 in the repetitive model, suggesting expansion of a bronchoalveolar stem cell-like population. In reporter mice, 50% of S100A4+ lung fibroblasts were derived from epithelial mesenchymal transition compared with 33% in the single-dose model. With repetitive bleomycin, fibrotic remodeling persisted 10 wk after the eighth dose. Repetitive intratracheal bleomycin results in marked lung fibrosis with prominent AEC hyperplasia, features reminiscent of UIP.

SUBMITTER: Degryse AL

PROVIDER: S-EPMC2957416 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis.

Degryse Amber L AL Tanjore Harikrishna H Xu Xiaochuan C XC Polosukhin Vasiliy V VV Jones Brittany R BR McMahon Frank B FB Gleaves Linda A LA Blackwell Timothy S TS Lawson William E WE

American journal of physiology. Lung cellular and molecular physiology 20100618 4

Single-dose intratracheal bleomycin has been instrumental for understanding fibrotic lung remodeling, but fails to recapitulate several features of idiopathic pulmonary fibrosis (IPF). Since IPF is thought to result from recurrent alveolar injury, we aimed to develop a repetitive bleomycin model that results in lung fibrosis with key characteristics of human disease, including alveolar epithelial cell (AEC) hyperplasia. Wild-type and cell fate reporter mice expressing β-galactosidase in cells of ...[more]

PMID: 20562227

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Project description:UnlabelledIdiopathic pulmonary fibrosis is an inexorably progressive lung disease with few available treatments. New therapeutic options are needed. Stem cells have generated much enthusiasm for the treatment of several conditions, including lung diseases. Human trials of mesenchymal stromal cell (MSC) therapy for pulmonary fibrosis are under way. To shed light on the potential usefulness of MSCs for human disease, we aimed to systematically review the preclinical literature to determine if MSCs are beneficial in animal bleomycin pulmonary fibrosis models. The MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal bleomycin models of pulmonary fibrosis. Studies using embryonic stem cells or induced pluripotent stem cells were excluded. Seventeen studies were selected, all of which used MSCs in rodents. MSC therapy led to an improvement in bleomycin-induced lung collagen deposition in animal lungs and in the pulmonary fibrosis Ashcroft score in most studies. MSC therapy improved histopathology in almost all studies in which it was evaluated qualitatively. Furthermore, MSC therapy was found to improve 14-day survival in animals with bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage total and neutrophil counts, as well as transforming growth factor-β levels, were also reduced by MSCs. MSCs are beneficial in rodent bleomycin pulmonary fibrosis models. Since most studies examined the initial inflammatory phase rather than the chronic fibrotic phase, preclinical data offer better support for human trials of MSCs in acute exacerbations of pulmonary fibrosis rather than the chronic phase of the disease.SignificanceThere has been increased interest in mesenchymal stromal cell therapy for lung diseases. A few small clinical trials are under way in idiopathic pulmonary fibrosis. Preclinical evidence was assessed in a systematic review, as is often done for clinical studies. The existing studies offer better support for efficacy in the initial inflammatory phase rather than the fibrotic phase that human trials are targeting.

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Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis.

Publications

Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis.

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