Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia.

E.R Parra,A.P.P Velosa,V.L Capelozzi,M.P Rangel,M.S Pincelli,W.R Teodoro,V Martins,J.V Barbas-Filho

doi:10.1590/1414-431x20143522

Abstract

Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung pneumonia of unknown cause that typically increases in prevalence with advanced age, presumably from repeated episodes of injury, repair, and scarring that lead to dramatic changes in the lung architecture and progressive respiratory failure [1]
We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration
To validate the importance of the telomerase/apoptosis index and collagen V synthesis and to explore the quantitative relationships between these factors and epithelial proliferation, vascularization, and fibrosis, we studied these markers in an experimental simulated human usual interstitial pneumonia (UIP) model induced in mice by 3-5-di-tert-butyl-4-hydroxytoluene (BHT)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung pneumonia of unknown cause that typically increases in prevalence with advanced age, presumably from repeated episodes of injury, repair, and scarring that lead to dramatic changes in the lung architecture and progressive respiratory failure [1]. There is great interest in understanding the mechanisms of tissue damage from repair and scarring, because if treatment is to be effective, one must identify these pathogenic mechanisms to avoid fibrosis and destruction of the lungs. The repair process involves distinct stages including a regenerative phase in which the microenvironment attempts to replace apoptotic epithelial cells, new vascularization, and a fibrotic phase in which collagen fibers replace normal parenchymal tissue [4,5,6]. It is initially beneficial, failure to control the healing process can lead

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