cyclin-d1 and Lung-Diseases

Topics: Biomarkers; Cyclin D1; Histiocytosis, Langerhans-Cell; Humans; Immunohistochemistry; Lung Diseases; Proto-Oncogene Proteins B-raf; Sensitivity and Specificity

α(2)-Adrenoceptors belong to the family of adrenergic receptors, which regulate the neuronal release of norepinephrine as part of a negative feedback loop. Among the α(2)-adrenoceptors, the α(2B)-subtype may also influence developmental signaling pathways involved in angiogenesis of the placenta. Thus, the aim of the present study was to determine whether α(2B)-adrenoceptors are also involved in other developmental processes beyond placental angiogenesis. Ablation of α(2B)-adrenoceptors led to lethality of mutant mice during the first hours after birth. Despite normal breathing and drinking behavior, mutant mice developed cyanosis, which could be traced back to a defect in lung morphology with significantly reduced alveolar volume and thickened interalveolar septi. In α(2B)-deficient lungs and in isolated alveolar type II cells, expression of sonic hedgehog (SHH) was significantly increased, resulting in mesenchymal proliferation. In vitro α(2B)-adrenoreceptor stimulation suppressed expression of sonic hedgehog and the cell cycle genes cyclin D1 and Ki67. In vivo inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine partially rescued perinatal lethality, lung morphology, and altered gene expression in mutant mice. Thus, α(2B)-adrenoceptors in lung epithelia play an important role in suppressing sonic hedgehog-mediated proliferation of mesenchymal cells and thus prevent respiratory failure.

Topics: Animals; Cyclin D1; Disease Models, Animal; Epithelium; Hedgehog Proteins; Heterozygote; Ki-67 Antigen; Lung; Lung Diseases; Mesoderm; Mice; Mice, Inbred C57BL; Neurotransmitter Agents; Receptors, Adrenergic, alpha-2; Veratrum Alkaloids

This report details the pulmonary pathologic findings in four patients with rheumatoid arthritis, who developed new onset of pulmonary signs and symptoms with alveolar infiltrates temporally related to the institution of etanercept therapy. Biopsy findings showed an interstitial and air space lymphohistiocytic infiltrate with non-necrotizing granulomas, in the setting of negative cultures and special stains for microorganisms. The association with etanercept therapy and granulomatous reactions is discussed along with the differential diagnosis.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antirheumatic Agents; Arthritis, Rheumatoid; CD3 Complex; CD5 Antigens; Cough; Cyclin D1; Diagnosis, Differential; Dyspnea; Etanercept; Female; Granuloma; Histiocytes; Humans; Immunoglobulin G; Immunohistochemistry; Leukosialin; Lung Diseases; Lymphocytes; Middle Aged; Receptors, Tumor Necrosis Factor; Sialoglycoproteins

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.

Topics: Adolescent; Adult; Aged; Antigens, Neoplasm; Apoptosis; Cell Division; Child; Cyclin D1; DNA Topoisomerases, Type II; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Isoenzymes; Lung Diseases; Male; Middle Aged; Prognosis; Proto-Oncogene Proteins c-myc; Pulmonary Alveoli