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(Chest. 2001;120:S33-S34.)
© 2001 American College of Chest Physicians

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 and Gilbert F. Morris, PhD

* 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{at}tulane.edu

Key Words: asbestos • epithelial growth factor receptor • fibrosis • p53 • transforming growth factor-{alpha}

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)-{alpha},3 4 and its receptor, epidermal growth factor receptor (EGF-R).5 6 7 Thus, activation of p53 expression by asbestos may initiate an autocrine/paracrine loop that stimulates fibrogenesis. Rapid activation of both p53 and TGF-{alpha} 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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  		Figure 1. Histopathologic scores for asbestos-exposed SPC-DNp53 transgenic mice and their nontransgenic littermates. Transgenic and nontransgenic mice from three separate exposures were killed at 2 days or 3 days after exposure and lung sections were prepared.8 Three independent observers, unaware of the sample identity, evaluated the hematoxylin-eosin–stained lung sections for asbestos-induced histopathologic damage. Histologic scores are the median value for the section from each mouse.

 
In an alternative approach to assess p53 function in the lung epithelium after exposure to asbestos, mice that overexpress wild-type p53 from the surfactant protein C promoter, SPC-wtp53 transgenic mice, and nontransgenic littermates were exposed to an aerosol of asbestos fibers on 3 consecutive days for 5 h each day. In previous experiments, this exposure protocol produced marked development of fibrogenic lesions and prolonged incorporation of bromodeoxyuridine into lung cells.9 One week after the last exposure, the mice were killed and fixed lung tissue was processed for histologic examination. The high dose of asbestos produced more severe fibrogenesis in SPC-wtp53 transgenic mice than simultaneously exposed nontransgenic littermates (not shown). These results are consistent with our postulate that activation of p53 intensifies the fibrogenic response to inhaled asbestos. Preliminary analyses of TGF-{alpha} and EGF-R messenger RNA expression in the asbestos-exposed transgenic and nontransgenic mice suggest that induction of a TGF-{alpha}–EGF-R autocrine loop in the lung epithelium by p53 accounts, in part, for the fibrogenic response to inhaled asbestos.

Footnotes

Abbreviations: EGF = epidermal growth factor receptor; SPC = DNp53 = surfactant protein C-dominant negative p53; SPC-wtp53 = surfactant protein C–wild-type p53; TGF = transforming growth factor

Supported by National Institutes of Health grants ES07856, ES08628, and the Department of Defense-Tulane/Xavier Center for Bioenvironmental Research. Anne Nelson received matching support from the Tulane Cancer Center.

References

  1. Mishra, A, Liu, JY, Brody, AR, et al (1997) Inhaled asbestos fibers induce p53 expression in the rat lung. Am J Respir Cell Mol Biol 16,479-485[Abstract]
  2. Morris, GF, Hoyle, GW, Athas, GB, et al (1998) Lung-specific expression in mice of a dominant negative mutant form of the p53 tumor suppressor protein. J La State Med Soc 150,179-185[Medline]
  3. Shin, TH, Paterson, AJ, Kudlow, JE (1995) p53 stimulates transcription from the transforming growth factor alpha promoter: a potential growth-stimulatory role for p53. Mol Cell Biol 15,4694-4701[Abstract]
  4. Korfhagen, TR, Swantz, RJ, Wert, SE, et al (1994) Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J Clin Invest 4,1691-1699
  5. Ludes-Meyers, JH, Subler, MA, Shivakumar, CV, et al (1996) Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol 16,6009-6019[Abstract]
  6. Sheikh, MS, Carrier, F, Johnson, SE, et al (1997) Identification of an additional p53-responsive site in the human epidermal growth factor receptor gene promotor. Oncogene 15,1095-1101[CrossRef][Medline]
  7. Hardie, WD, Kerlakian, CB, Bruno, MD, et al (1996) Reversal of lung lesions in transgenic transforming growth factor-{alpha} mice by expression of mutant epidermal growth factor receptor. Am J Respir Cell Mol Biol 15,499-508[Abstract]
  8. Liu, J-Y, Morris, GF, Lei, W-H, et al (1996) Upregulated expression of transforming growth factor-{alpha} in the bronchiolar-alveolar duct regions of asbestos-exposed rats. Am J Pathol 149,205-217[Abstract]
  9. Coin, PC, Osorino-Vargas, A, Moore, L, et al (1996) Pulmonary fibrogenesis after three consecutive inhalation exposures to chrysotile asbestos. Am J Respir Crit Care Med 154,1511-1519[Abstract]



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