State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: an evolutionary perspective

Abstract

Emphysema consists of a unique pattern of alveolar destruction, resulting in marked airspace enlargement with reduction of alveolar capillary exchange area. Classical concepts of the pathogenesis of emphysema have relied on the paradigm set by the inflammation and protease/antiprotease imbalance. We propose herein that cigarette smoke constitutes an environmental hazard that causes alveolar destruction by the interaction of apoptosis, oxidative stress, and protease/antiprotease imbalance. We draw a parallel between organismal aging, organ structural maintenance, and the damage resulting from chronic cigarette smoke inhalation. The stochastic interaction between environmental hazards and the effort of an organism or a particular organ to fend off these hazards results in the accumulation of cellular damage and features characteristic of aging. Inflammation follows as the result of the multiplication of injuries. We highlight the importance of understanding the biology of the interaction of alveolar cells in homeostasis and in alveolar destruction, and the potential role of novel processes related to senescence and stress response. An evolutionary perspective of emphysema that incorporates mechanisms related to aging may lead to important advances in the understanding and therapeutic targeting of chronic obstructive pulmonary disease.

Figure 1.

Conceptual framework for emphysema. Cigarette smoke causes a progressive disruption of alveolar maintenance and variable degrees of inflammation, driven by the cigarette smoke itself, oxidative stress, or alveolar cell damage. After years of relentless attack by this underlying process counterbalanced by potential repair, susceptible individuals would activate molecular and cellular processes involved in alveolar destruction, namely protease/antiprotease imbalance, apoptosis, and oxidative stress. These processes are mutually interactive, and promote amplifying feed-foward loops. Endogenous mediators such as ceramide would promote the amplification of these processes, increasing inflammatory cell injury and hampering repair processes. Several of these elements are also present in organismal aging.

Figure 2.

Comparison between human lung pathology caused by infectious agents and that caused by cigarette smoke. Morphologic comparison of lung inflammation caused by infectious agents (a–c), showing acute bacterial pneumonia (a), a gross lung section with a cavitary fungal lesion (b), and microscopic highlight of cytomegalovirus pneumonia (c). The respective infectious agents that cause these pathologies are highlighted in d–f. On the other hand, cigarette smoke (h) causes the characteristic alveolar loss (i) and the characteristic simplification of alveolar septa with airspace enlargement (j).

Figure 3.

Kirkwood model of aging based on the concept of “disposable soma.” Reprinted by permission from Reference .

Figure 4.

Ceramide causes emphysema-like changes. Intratracheal ceramide instillation causes airspace enlargement as described in Reference with evidence of alveolar cell apoptosis highlighted by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) on Day 1 postinstillation (top right panel). +ctl = positive control with endonuclease DNA cleavage and TUNEL; −ctl = negative control with TUNEL lacking DNA polymerase. Botton panel highlights alveolar cell apoptosis with double fluorescence for apoptotic cells (green) and nuclei (4,6 diamidino-2 pheylindole [DAPI], blue).