Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP)

J V Barbas-Filho, M A Ferreira, A Sesso, R A Kairalla, C R R Carvalho, V L Capelozzi

The Department of Pathology, University of São Paulo School of Medicine, São Paulo, CEP 01250–020, Brazil
Pulmonary Division, University of São Paulo School of Medicine

Correspondence to:
Professor Barbas-Filho, Faculdade de Medicina da USP, Departamento de Patologia, Rua Theodoro Ramos 303, CEP 01250–020, São Paulo, SP, Brasil vcapelozzi{at}.lim05.fm.usp.br

Background/Aims—The pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), a chronic and incurable human respiratory disease, is not well established. This study was designed to investigate whether the apoptosis of type II pneumocytes could be the precipitating factor in the pathogenesis of IPF.

Methods—Nineteen specimens obtained by retrospective review of the medical and pathological records of 55 patients with IPF, four normal subjects, and 10 disease control lungs were analysed. The selected specimens had normal alveoli with intervening patchy scarring of the lung parenchyma, fulfilling the pathological criteria for UIP. To identify individual cells undergoing apoptosis in the normal alveoli, electron microscopy and in situ end labelling of fragmented DNA were performed on paraffin wax embedded sections using digoxigenin-11-dUTP and the enzyme terminal deoxynucleotidyl transferase.

Results—Apoptosis was detected in the normal alveoli of 17 of the 19 patients with IPF/UIP and was absent in the controls. Electron microscopy demonstrated apoptotic changes in type II pneumocytes. These results indicate that apoptotic type II pneumocyte death occurs in normal alveoli of IPF/UIP and could be the principal cause of several events that account for the histological, clinical, and functional alterations seen in IPF/UIP.

Conclusions—In conclusion, numerous type II pneumocytes from the normal alveoli of most patients with IPF/UIP actively undergo programmed cell death. This finding may shed new light on the pathogenesis of this disease, with implications mainly for the treatment of affected patients.

Key Words: apoptosis • type II pneumocytes • idiopathic pulmonary fibrosis • pathogenesis

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Oikonomou, N, Thanasopoulou, A, Tzouvelekis, A, Harokopos, V, Paparountas, T, Nikitopoulou, I, Witke, W, Karameris, A, Kotanidou, A, Bouros, D, Aidinis, V (2009). Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis. Thorax 64: 467-475 [Abstract] [Full Text]  
• Uhal, B. D. (2008). The role of apoptosis in pulmonary fibrosis. ERR 17: 138-144 [Abstract] [Full Text]  
• Korfei, M., Ruppert, C., Mahavadi, P., Henneke, I., Markart, P., Koch, M., Lang, G., Fink, L., Bohle, R.-M., Seeger, W., Weaver, T. E., Guenther, A. (2008). Epithelial Endoplasmic Reticulum Stress and Apoptosis in Sporadic Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 178: 838-846 [Abstract] [Full Text]  
• Kurosu, K., Takiguchi, Y., Okada, O., Yumoto, N., Sakao, S., Tada, Y., Kasahara, Y., Tanabe, N., Tatsumi, K., Weiden, M., Rom, W. N., Kuriyama, T. (2008). Identification of Annexin 1 as a Novel Autoantigen in Acute Exacerbation of Idiopathic Pulmonary Fibrosis. J. Immunol. 181: 756-767 [Abstract] [Full Text]  
• Clement, A., Eber, E. (2008). Interstitial lung diseases in infants and children. Eur Respir J 31: 658-666 [Abstract] [Full Text]  
• Willis, B. C., Borok, Z. (2007). TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L525-L534 [Abstract] [Full Text]  
• du Bois, R. M. (2007). Blocking endothelin: breaking new ground. ERR 16: 24-29 [Abstract] [Full Text]  
• Fridlender, Z. G., Cohen, P. Y., Golan, O., Arish, N., Wallach-Dayan, S., Breuer, R. (2007). Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis. Eur Respir J 30: 205-213 [Abstract] [Full Text]  
• Roger Parra, E., Adib Kairalla, R., de Carvalho, C. R. R., Capelozzi, V. L. (2007). Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias. Thorax 62: 428-437 [Abstract] [Full Text]  
• Golan-Gerstl, R., Wallach-Dayan, S. B., Amir, G., Breuer, R. (2007). Epithelial Cell Apoptosis by Fas Ligand-Positive Myofibroblasts in Lung Fibrosis. Am. J. Respir. Cell Mol. Bio. 36: 270-275 [Abstract] [Full Text]  
• Thannickal, V. J., Horowitz, J. C. (2006). Evolving concepts of apoptosis in idiopathic pulmonary fibrosis.. Proc Am Thorac Soc 3: 350-356 [Abstract] [Full Text]  
• Selman, M., Pardo, A. (2006). Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers.. Proc Am Thorac Soc 3: 364-372 [Abstract] [Full Text]  
• Martin, T. R., Hagimoto, N., Nakamura, M., Matute-Bello, G. (2005). Apoptosis and Epithelial Injury in the Lungs. Proc Am Thorac Soc 2: 214-220 [Abstract] [Full Text]  
• Nakashima, N, Kuwano, K, Maeyama, T, Hagimoto, N, Yoshimi, M, Hamada, N, Yamada, M, Nakanishi, Y (2005). The p53-Mdm2 association in epithelial cells in idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. J. Clin. Pathol. 58: 583-589 [Abstract] [Full Text]  
• Matsuyama, W., Watanabe, M., Shirahama, Y., Oonakahara, K.-i., Higashimoto, I., Yoshimura, T., Osame, M., Arimura, K. (2005). Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis. J. Immunol. 174: 6490-6498 [Abstract] [Full Text]  
• Plataki, M., Koutsopoulos, A. V., Darivianaki, K., Delides, G., Siafakas, N. M., Bouros, D. (2005). Expression of Apoptotic and Antiapoptotic Markers in Epithelial Cells in Idiopathic Pulmonary Fibrosis. Chest 127: 266-274 [Abstract] [Full Text]  
• Miyazaki, H, Kuwano, K, Yoshida, K, Maeyama, T, Yoshimi, M, Fujita, M, Hagimoto, N, Yoshida, R, Nakanishi, Y (2004). The perforin mediated apoptotic pathway in lung injury and fibrosis. J. Clin. Pathol. 57: 1292-1298 [Abstract] [Full Text]  
• Watts, K. L., Spiteri, M. A. (2004). Connective tissue growth factor expression and induction by transforming growth factor-{beta} is abrogated by simvastatin via a Rho signaling mechanism. Am. J. Physiol. Lung Cell. Mol. Physiol. 287: L1323-L1332 [Abstract] [Full Text]  
• Li, X., Shu, R., Filippatos, G., Uhal, B. D. (2004). Apoptosis in lung injury and remodeling. J. Appl. Physiol. 97: 1535-1542 [Abstract] [Full Text]  
• Nadrous, H. F., Ryu, J. H., Douglas, W. W., Decker, P. A., Olson, E. J. (2004). Impact of Angiotensin-Converting Enzyme Inhibitors and Statins on Survival in Idiopathic Pulmonary Fibrosis. Chest 126: 438-446 [Abstract] [Full Text]  
• Inoshima, I., Kuwano, K., Hamada, N., Yoshimi, M., Maeyama, T., Hagimoto, N., Nakanishi, Y., Hara, N. (2004). Induction of CDK inhibitor p21 gene as a new therapeutic strategy against pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 286: L727-L733 [Abstract] [Full Text]  
• Kaminski, N., Belperio, J. A., Bitterman, P. B., Chen, L., Chensue, S. W., Choi, A. M.K., Dacic, S., Dauber, J. H., du Bois, R. M., Enghild, J. J., Fattman, C. L., Grutters, J. C., Haegens, A., Hanford, L. E., Heintz, N., Henson, P. M., Hogaboam, C., Kagan, V. E., Keane, M. P., Kunkel, S. L., Land, S., Loyd, J. E., Lukacs, N., MacPherson, M., Manning, B., Manning, N., Martinelli, M., Moller, D. R., Morse, D., Mossman, B., Noble, P. W., Nowak, N., Oury, T. D., Pardo, A., Perez, A., Petty, T. L., Phan, S. H., Ramos-Nino, M. E., Ray, P., Rogers, R. M., Sato, H., Scapoli, L., Schaefer, L. M., Selman, M., Stern, M., Strollo, D. C., Tyurin, V. A., Valnickova, Z., Welsh, K. I., Witzmann, F. A., Yousem, S. A., Strieter, R. M. (2003). Idiopathic Pulmonary Fibrosis. Am. J. Respir. Cell Mol. Bio. 29: S1-105 [Full Text]  
• Atkinson, J. J., Senior, R. M. (2003). Matrix Metalloproteinase-9 in Lung Remodeling. Am. J. Respir. Cell Mol. Bio. 28: 12-24 [Abstract] [Full Text]  
• Koyama, S., Sato, E., Haniuda, M., Numanami, H., Nagai, S., Izumi, T. (2002). Decreased Level of Vascular Endothelial Growth Factor in Bronchoalveolar Lavage Fluid of Normal Smokers and Patients with Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 166: 382-385 [Abstract] [Full Text]