Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models

The cellular mechanisms that result in the initiation and progression of emphysema are clearly complex. A growing body of human data combined with discoveries from mouse models utilizing cigarette smoke exposure or protease administration have improved our understanding of emphysema development by implicating specific cell types that may be important for the pathophysiology of chronic obstructive pulmonary disease. The most important aspects of emphysematous damage appear to be oxidative or protease stress and sustained macrophage activation and infiltration of other immune cells leading to epithelial damage and cell death. Despite the identification of these associated processes and cell types in many experimental studies, the reasons why cigarette smoke and other pollutants result in unremitting damage instead of injury resolution are still uncertain. We propose an important role for macrophages in the sequence of events that lead and maintain this chronic tissue pathologic process in emphysema. This model involves chronic activation of macrophage subtypes that precludes proper healing of the lung. Further elucidation of the cross-talk between epithelial cells that release damage-associated signals and the cellular immune effectors that respond to these cues is a critical step in the development of novel therapeutics that can restore proper lung structure and function to those afflicted with emphysema.