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. 2001 Feb;54(2):132–138. doi: 10.1136/jcp.54.2.132

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

J Barbas-Filho 1, M Ferreira 1, A Sesso 1, R Kairalla 1, C Carvalho 1, V Capelozzi 1
PMCID: PMC1731356  PMID: 11215282

Abstract

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

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Figure 1 Lung parenchyma of patients with usual interstitial pneumonia. (A) Characteristic variation in histological appearance from one area to another. Dense collagen deposition in the lung parenchyma is seen on the left, and patchy areas containing normal or nearly normal alveoli are present nearby (right and bottom centre). There is a zone of microscopic honeycomb change at the middle left (arrowheads) that is characterised by mucin filled, enlarged air spaces separated by fibrosis (haematoxylin and eosin staining; magnification, x100). (B) High magnification view of the surviving zones of alveoli showing marginated masses of chromatin within shaped, rounded alveolar cells with eosinophilic cytoplasm (arrowheads), suggestive of type II pneumocytes (haematoxylin and eosin staining; magnification, x400).

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Figure 2 In situ end labelling of fragmented DNA with terminal deoxynucleotidyl transferase and digoxigenin-11-dUTP. Cells with fragmented DNA stained brown, whereas cells with normal nuclei stained blue (immunoperoxidase staining with haematoxylin counterstaining). (A) A section from a normal lung shows no apoptotic nuclei (magnification, x160). The intra-alveolar cells seen are macrophages containing carbon pigment (arrowheads). (B) Lung sections from patients with usual interstitial pneumonia (magnification, x400) with increased labelling. Numerous alveolar nuclei undergoing apoptosis suggestive of type II pneumocytes (arrowheads).

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Figure 3 Sections of lung from patients with usual interstitial pneumonia examined by electron microscopy. (A) Type II pneumocytes undergoing non-explicit apoptosis, characterised by fine and uniformly dispersed chromatin within the nuclear membrane. These pneumocytes have swollen mitochondrial profiles, sometimes with rupture of the outer membrane because of the pressure of the inner mitochondrial membrane, which surrounds a greatly swollen inner mitochondrial compartment (arrows and arrows heads). (B and C) Type II pneumocytes with very different nuclear profiles to those of non-apoptotic cells, characterised by progressive condensation of the chromatin as part of a clarifying process of the remaining nuclear region and a final degradation of the cytoplasmic structure (magnification, x9000).

Selected References

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