What drives the peripheral lung-remodeling process in chronic obstructive pulmonary disease?

Abstract

The smaller airways (<2 mm in diameter) offer little resistance in normal lungs but become the major site of obstruction in chronic obstructive pulmonary disease (COPD). We examined bronchiolar remodeling in COPD by combining quantitative histology, micro-computed tomography (CT), and gene expression studies. Volumes of bronchiolar tissue, total collagen, collagen-1, and collagen-3 were measured in lung tissue from 52 patients with different levels of COPD severity. Micro-CT was used to measure the number and lumen area of terminal bronchioles in four lungs removed before lung transplantation and in four donor lungs that served as controls. Laser capture microdissection provided 136 paired samples of bronchiolar and surrounding lung tissue from 63 patients and the gene expression of a cluster of tissue repair genes was compared. This study shows that total bronchiolar tissue decreased with progression of COPD and was associated with a reduction in total collagen and relative increase in collagen-3 over collagen-1. The micro-CT studies showed a 10-fold reduction in terminal bronchiolar number and a 100-fold reduction in lumen area. Interestingly, most genes associated with tissue accumulation during repair decreased their expression in both airways and in the surrounding lung as FEV(1) declined, but eight genes previously associated with COPD increased expression in the surrounding lung tissue. Our study shows that small airway remodeling is associated with narrowing and obliteration of the terminal bronchioles that begins before emphysematous destruction in COPD and in relation to differential expression of tissue repair genes in the airways and surrounding lung.

Figure 1.

The remodeling of repetitively damaged tissue. Shown is a comparison of collagen accumulation in a wound predicted from measurements of the rate of labeled hydroxyproline incorporation (upper curve) and actual values (lower curve). Difference between curves (brackets) indicates that deposition is determined by a balance between synthesis and degradation. Adapted by permission from Reference 26.

Figure 2.

The repair of repetitively damaged tissue. Shown is a diagram modified from Robbins and Cotran (1) to indicate that tobacco smoking is similar to other forms of repetitive injury in that it results in a persistent inflammatory response. Moreover, the cells participating in the persistent inflammatory process generate the transcription factors, growth factors, cytokines, and enzymes required to create the balance between collagen synthesis and degradation that determines the deposition of collagen in the tissue undergoing repair growth. The essence of our working hypothesis is that in the peripheral lung this balance favors deposition of collagen in the damaged bronchiolar tissue in the early stages of chronic obstructive pulmonary disease. However, this balance shifts toward degradation of the terminal bronchioles, leaving relatively thickened airways behind as the process spreads into the respiratory bronchioles to initiate emphysematous destruction.