The cellular and molecular determinants of emphysematous destruction in COPD

Masaru Suzuki,John F Brothers,Joel D Cooper,Avrum Spira,Marc E Lenburg,John E Mcdonough,Joshua D Campbell,James C Hogg,W Mark Elliott,Marc A Sze

doi:10.1038/s41598-017-10126-2

Abstract

The introduction of microCT has made it possible to show that the terminal bronchioles are narrowed and destroyed before the onset of emphysematous destruction in COPD. This report extends those observations to the cellular and molecular level in the centrilobular phenotype of emphysematous destruction in lungs donated by persons with very severe COPD (n = 4) treated by lung transplantation with unused donor lungs (n = 4) serving as controls. These lung specimens provided companion samples to those previously examined by microCT (n = 61) that we examined using quantitative histology (n = 61) and gene expression profiling (n = 48). The histological analysis showed that remodeling and destruction of the bronchiolar and alveolar tissue is associated with macrophage, CD4, CD8, and B cell infiltration with increased formation of tertiary lymphoid organs. Moreover, gene set enrichment analysis showed that genes known to be expressed by natural killer (NK), lymphoid tissue inducer (LTi), and innate lymphoid cell 1 (ILC1) cells, but not ILC2 or ILC3 cells, were enriched in the expression profiles associated with CD4, CD8, and B cell infiltration. Based on these findings, we postulate that the centrilobular phenotype of emphysematous destruction COPD is driven by a Th1 response activated by infiltrating ILC1, NK, and LTi cells.

Highlights

The decline in lung function used to measure the progression of chronic obstructive pulmonary disease (COPD) has frequently been linked to the infiltration of lung tissues by polymorphonuclear leukocytes (PMNs), macrophages, CD4, CD8, and B cell lymphocytes[1,2,3,4,5,6]
This destructive remodeling process is associated with a significant increase in ratio of collagen I to III in both tissues compared to the control lungs (Fig. 1C,D, Supplementary Figure S1B,C). These findings are consistent with scar formation in these tissues before the emphysematous lesions became large enough to be visible on thoracic multi-detector computed tomography (MDCT) scans
They showed that destruction of the terminal bronchioles precedes the onset emphysematous destruction measured by microCT and that the destruction of the terminal bronchioles is well established when the emphysematous lesions become large enough to be visualized on thoracic MDCT scans

Summary

Introduction

The decline in lung function used to measure the progression of chronic obstructive pulmonary disease (COPD) has frequently been linked to the infiltration of lung tissues by polymorphonuclear leukocytes (PMNs), macrophages, CD4, CD8, and B cell lymphocytes[1,2,3,4,5,6]. Once considered a curiosity, this pattern of progressively increasing macrophage, CD4, CD8, and B cell lymphocyte infiltration with tertiary lymphoid organ formation is recognized to be a fundamental pathological process that links the host inflammatory immune response to a destructive form of tissue repair[8]. This type of tissue response may be either beneficial to the host by combating invasive tumors and infections or detrimental to the host by initiating tissue destruction in many different organs[8] and possibly peripheral lung tissue in COPD5–7. The purpose of this report is to examine the relationship between these infiltrating inflammatory immune cells and the remodeling and destruction of both bronchiolar and alveolar tissues in the earliest stages of emphysematous destruction before the lesions become large enough to be visualized on thoracic multi-detector computed tomography (MDCT) scans

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Conclusion