Alteration of Fibroblast Architecture and Loss of Basal Lamina Apertures in Human Emphysematous Lung

Abstract

Rationale:In normal human lung, single alveolar fibroblasts link capillary endothelium to type 2 pneumocytes through apertures in the endothelial and epithelial basal laminae. These fibroblasts are hypothesized to play a role in cellular communication between the endothelium and epithelium and are positioned to provide leukocytes a surface on which they may migrate through the interstitium. Objectives: To determine whether fibroblasts link the endothelium to the epithelium in emphysematous lung and to compare basal lamina aperture frequency with previously published results. Methods: We performed transmission electron microscopy serial section three-dimensional reconstructions of emphysematous regions of human alveolar wall and a quantitative analysis of basal lamina apertures beneath 403 type 2 pneumocytes. Measurements and Main Results: Our three-dimensional reconstruction demonstrated that the fibroblasts subtending type 2 pneumocytes in emphysematous lung no longer link these epithelial cells to the capillary endothelium through basal lamina apertures. Basal lamina apertures may be absent below some type 2 pneumocytes. Our morphometric analysis showed that their frequency and area beneath type 2 pneumocytes is significantly reduced in emphysematous regions when compared with nonemphysematous regions of matched control lung. Conclusions: We conclude that the endothelial/fibroblast/epithelial linkage is disrupted in emphysematous human lungs and postulate this disruption may disturb leukocyte migration and account for their accumulation in the alveolar interstitium of emphysematous lung tissue.

Dysregulation of elastin expression by fibroblasts in pulmonary emphysema: role of cellular retinoic acid binding protein 2

“…The AP-2 transcription factor17 and protein kinase C18 have also been involved in the regulation of CRABP2 expression, but their role in pulmonary emphysema is unknown. Whatever the mechanism of the reduced CRABP2 expression in fibroblasts from patients with emphysema, the present results are in line with previous reports showing that the phenotype of lung fibroblasts is deeply altered in the emphysematous lung, as those cells have been shown to express markers of cellular senescence,19 to have a reduced proliferation rate20 and to secrete low amounts of hepatocyte growth factor, a key mitogen for alveolar epithelial cells,12 while they fail to link the endothelial and epithelial compartments of the lung through direct intercellular contacts, as is observed in the normal lung 21…”

Lung Fibroblast Repair Functions in Patients with Chronic Obstructive Pulmonary Disease Are Altered by Multiple Mechanisms

“…The current study assessed function of fibroblasts cultured from the pulmonary parenchyma and therefore is most likely relevant to emphysema rather than airway disease. Several studies suggest that the functional phenotype of fibroblasts in the airways may differ from that of the pulmonary parenchyma (61,62). Inhibition of fibrotic responses has been suggested as a means to prevent the progression of disease in the small airways.…”

Ultrastructural changes in atherosclerotic plaques following the instillation of airborne particulate matter into the lungs of rabbits

“…These images were captured at ×37,000 magnification, and then manually aligned and traced in Photoshop before application of three-dimensional reconstruction software (T3D, Research Systems Inc, USA). A similar protocol has been used previously to reconstruct the alveolar wall (42). SEM: These samples were chemically dried using hexamethyldisilazane (Sigma-Aldrich Inc, USA) in a BioWave Microwave (Pelco International, USA) (43).…”