Role of lung maintenance program in the heterogeneity of lung destruction in emphysema

Abstract

Centrilobular emphysema caused by chronic cigarette smoking is a heterogeneous disease with a predominance of upper lobe involvement. It is presumed that this heterogeneity indicates a particular susceptibility to cigarette smoke or the fact that the inhaled smoke distributes preferentially to upper lung zones. The less involved areas might therefore retain the capacity for lung regeneration and gain of pulmonary function in terminally ill patients. We propose that the interplay between molecular and cellular switches involved in the lung response to environmental injuries determines the heterogeneous pattern of emphysema due to cigarette smoke. Regional activation of alveolar destruction by apoptosis and oxidative stress coupled with regional failure of defense mechanisms may account for the irregular pattern of lung destruction in cigarette smoke-induced emphysema. Protection afforded by the key antioxidant transcription factor Nrf-2 and the antiproteolytic and antiapoptotic actions of alpha(1)-antitrypsin is central to maintain lung homeostasis and lung structure. As the lung is injured by environmental pollutants, including cigarette smoke, molecular sensors of cellular stress, such as the mTOR/protein translation regulator RTP-801, may engage both inflammation and alveolar cell apoptosis. As injury prevails during the course of this chronic disease, it leads to a more homogeneous pattern of lung disease.

Figure 1.

Conceptual framework of positive interaction among apoptosis, protease/antiprotease imbalance, and oxidative stress in emphysema.

Figure 2.

Evidence of a positive feedback loop between apoptosis and oxidative stress in lungs with emphysematous enlargement after vascular endothelial growth factor (VEGF) receptor blockade. A and B show the coexpression of a macromolecular of oxidative stress, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-HG; red signal) and apoptosis (black nuclear signal). In A, there is intense 8-HG expression in centrilobular areas (CL; arrows) with colocalization with active caspase-3. In B, the perilobular areas (PL) show less evidence of oxidative stress (arrows) and apoptosis (arrowheads). C shows the correlation between 8-HG intensity and caspase-3–positive cells. The graph illustrates the interactive loops between oxidative stress and apoptosis. Blockade of oxidative stress with an superoxide dismutase (SOD) mimetic led to significant decrease of oxidative stress, apoptosis, and alveolar enlargement (reproduced by permission from Reference 25).

Figure 3.

(A–C) Coexpression of markers of apoptosis and lung oxidative stress in experimental emphysema. The increased 8-HG expression in lungs with VEGF receptor blockade (A) is normalized in lungs cotreated with a broad-spectrum caspase inhibitor (B; normal lungs in C) (12, 25). The intensity of lung expression in the three groups is plotted in D. The graph illustrates that caspase inhibition leads to decrease in apoptosis, oxidative stress, and alveolar enlargement (reproduced by permission from Reference 25).

Figure 4.

Pathogenesis of α₁-antitrypsin (A1AT) deficiency. A1AT deficiency (ZZ variant) may lead to a more global alveolar destruction since it causes (1) oxidative stress via its proinflammatory properties when polymerized, (2) loss of the antiprotease shield, and (3) loss of anti–active caspase-3 activity (3, 43).

Figure 5.

RTP-801 and growth or inhibitory cell signaling in cells exposed to nutrients or environmental stresses, respectively. RTP-801 activates tubersclerosis complex hamartin and tuberin proteins (TSC1 and TSC2, respectively), which via inhibition of Rheb kinase lead to mTOR inhibition and suppression of protein translation. mTOR is usually activated under conditions favoring cell growth during abundance of nutrients or due to insulin signaling. The activation of RTP-801 is targeted for cell protection during stress; however, given the nature of the environmental stress, overexpression of RTP801 may cause apoptosis, oxidative stress, or excessive inflammation. AKT = protein kinase B; P-AKT = phosphorylated AKT; PI3K = phosphotidylinositol 3-kinase; RHEB-GTP = RHEB-GTPase.