title: Proliferation, C-myc, and cyclin D1 expression in diffuse alveolar damage: potential roles in pathogenesis and implications for prognosis.
abstract: In this study we compared expression of DNA topoisomerase IIalpha, a marker of cellular proliferation, c-myc, and cyclin D1 in lung biopsy specimens showing diffuse alveolar damage (DAD) with control lung tissues. We subsequently correlated DNA topoisomerase IIalpha, c-myc, and cyclin D1 expression with survival. We hypothesized that poor outcome may correlate with a higher proliferation index, and that c-myc and cyclin D1 activation are potentially important regulators of both proliferation and apoptosis in DAD. Immnuohistochemical stains for c-myc, cyclin D1, and DNA topoisomerase IIalpha were performed on 10 cases of DAD (15 cases for DNA topoisomerase IIalpha) and 10 control lungs. A proliferation index for each case was calculated by dividing the number of nuclei expressing DNA topoisomerase IIalpha by the total number of nuclei counted. The percentages of alveolar pneumocytes and interstitial cells staining positively for c-myc and cyclin D1 were estimated. The average proliferation index (DNA topoisomerase IIalpha index) in DAD (0.16 +/- 0.06, n = 15) was significantly greater than in control lungs (0.00 +/- 0.01, n = 10) (P < .0001). The average proliferation index of patients with DAD who died of respiratory failure (0.18 +/- 0.05, n = 9) was significantly greater than the average proliferation index of patients whose respiratory disease resolved or stabilized (0.11 +/- 0.05, n = 5) (P < .03). Expression of c-myc in alveolar pneumocytes and interstitial cells was more intense and slightly more widespread in cases of DAD compared with control lungs. In 9 of 10 cases of DAD, cyclin D1 expression was present in up to 30% of alveolar pneumocytes and up to 10% of interstitial cells. No staining for cyclin D1 was present in control lungs. These results show that the proliferation index in DAD potentially correlates with patient survival. Furthermore, enhanced expression of c-myc and cyclin D1 may contribute to dysregulation of cellular proliferation and apoptosis observed in DAD.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City 84132, USA.
authors.forename: A
authors.initials: A
authors.lastname: Adamson
authors.forename: S
authors.initials: S
authors.lastname: Perkins
authors.forename: E
authors.initials: E
authors.lastname: Brambilla
authors.forename: S
authors.initials: S
authors.lastname: Tripp
authors.forename: J
authors.initials: J
authors.lastname: Holden
authors.forename: W
authors.initials: W
authors.lastname: Travis
authors.forename: D
authors.initials: D
authors.lastname: Guinee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D017209:Apoptosis; D002455:Cell Division; D002648:Child; D019938:Cyclin D1 / Q000096:biosynthesis*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; D004250:DNA Topoisomerases, Type II