Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease associated with the histological appearance of usual interstitial pneumonia (UIP) in surgical lung biopsy. The histological pattern is characterized by alternating areas of normal parenchyma, alveolar collapse, honeycombing and severe mural organizing fibrosis, defined as sites of active remodelling overlying fibrous airspace walls, thus showing temporal heterogeneity, or overlying normal rigid pulmonary structures (e.g. interlobular septa) in the form of fibroblast foci and granulation tissue (American Thoracic Society/European Respiratory Society 2002). Idiopathic pulmonary fibrosis has several functional repercussions with limiting symptoms and results in important quality of life deterioration. In addition, the currently available treatments present minimal beneficial effects and cause significant side effects. Thus, the identification of the sequential mechanisms involved in the pathogenesis of IPF could help establish the adequate treatment or definitively block pulmonary remodelling. Recently, some authors have speculated that the structural remodelling in IPF that culminates in interstitial thickening has an early stage, secondary to epithelial type II pneumocyte (TIIp) apoptosis phenomenon, leading to alveolar collapse (Barbas-Filho et al. 2001; Baptista et al. 2006) and secondary exudative inflammation and a late stage with the incorporation of organizing intra-alveolar fibrosis (Basset et al. 1986), involving a degree of vascularization and endothelial activation (Parra et al. 2005). Despite advances in knowledge of the pathogenesis in IPF, the temporal evolution of epithelial, vascular and interstitial components of the pulmonary injury in human disease remains a matter of speculation, mainly in the face of sequential structural pulmonary remodelling. Finally, the identification of an experimental model with IPF that shares the morphologic fidelity with the human disease is rare in the existing medical literature, being the first step to establish a true model of the disease. This study was undertaken to test the hypothesis that structural remodelling of pulmonary parenchyma may be already altered early in IPF evolution. The structural changes would hypothetically reflect the alteration of the alveolar epithelium, microvasculature and connective fibre complex of the alveolar septa. The model and methods used demonstrate the progression of the disease, and result in remodelling within the lungs that is typical of IPF, providing an accurate way to evaluate the relationship between epithelial and interstitial remodelling (amount of type II pneumocytes, collagen and elastic fibres) at different stages of 3-5-di-tert-butyl-4-hydroxytoluene (BHT)-induced pulmonary injury.