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Enhancement of Fibrogenesis by the p53 Tumor Suppressor Protein in Asbestos-Exposed Rodents*

Anne Nelson, PhD; Tamra Mendoza, BS; Gary W. Hoyle, PhD; Arnold R. Brody, PhD; Cesar Fermin, PhD; Gilbert F. Morris, PhD
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*From the Program in Lung Biology, Departments of Pathology (Drs. Nelson, Brody, Fermin, and Morris, and Ms. Mendoza) and Medicine (Dr. Hoyle), Tulane University Medical Center, New Orleans, LA.

Correspondence to: Gilbert F. Morris, PhD, Department of Pathology, SL-79, Tulane University Medical Center, 1430 Tulane Ave, New Orleans, LA 70112; e-mail: gmorris2@tulane.edu



Chest. 2001;120(1_suppl):S33-S34. doi:10.1378/chest.120.1_suppl.S33
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Inhaled asbestos rapidly initiates fibrogenesis and concomitant expression of the p53 tumor suppressor protein at the sites of fiber deposition in the lungs of rodents.1 To assess the role of p53 in mouse asbestos inhalation models, we have developed transgenic mice with reduced (surfactant protein C–dominant negative p53 [SPC-DNp53]) or enhanced (surfactant protein C–wild-type p53 [SPC-wtp53]) p53 function specifically targeted within the pulmonary epithelium.2 Although primarily a suppressor of cell growth, p53 transcriptionally activates expression of an inducer of fibrosis, transforming growth factor (TGF)-α,34 and its receptor, epidermal growth factor receptor (EGF-R).57 Thus, activation of p53 expression by asbestos may initiate an autocrine/paracrine loop that stimulates fibrogenesis. Rapid activation of both p53 and TGF-α expression at the sites of fiber deposition after inhalation exposure of rodents to an aerosol of asbestos fibers correlates with amplification of the developing scar.1,8 To assess the function of p53 in the lung epithelium of asbestos-exposed mice, SPC-DNp53 transgenic mice and nontransgenic littermates were exposed to an aerosol of asbestos for 5 h. Two days or 3 days after exposure, the animals were killed and the histopathology of the lungs was evaluated. As shown in Figure 1, the histopathologic scores of asbestos-exposed SPC-DNp53 transgenic mice appeared to be reduced relative to those in simultaneously exposed nontransgenic littermates. These findings coincided with reduced bromodeoxyuridine incorporation into cells of the terminal bronchioles and the bronchiolar-alveolar duct bifurcations of the asbestos-exposed transgenic animals relative to nontransgenic control mice (not shown). Thus, incorporation of bromodeoxyuridine into developing fibroproliferative lesions and histopathologic assessments of these lesions demonstrate reduced fibrogenesis in asbestos-exposed transgenic mice expressing dominant negative p53 in the lung relative to that observed in simultaneously exposed nontransgenic littermates.

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