Inflammatory cells and mediators: A wide variety of inflammatory mediators have been shown to be increased (including leukotriene B4, IL-8, TNF, and others) that attract more inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors). The inflammatory cells present in lesions include neutrophils, macrophages, and CD4+ and CD8+ T cells. It is not known if the T cells are specific for a particular antigen or are recruited as part of inflammation.
Protease–anti-protease imbalance: Several proteases are released from the inflammatory cells and epithelial cells that break down connective tissues. In patients who develop emphysema, there is a relative deficiency of protective anti-proteases (further discussed below).
Oxidative stress: Reactive oxygen species are generated by cigarette smoke and other inhaled particles and released from activated inflammatory cells such as macrophages and neutrophils. These cause additional tissue damage and inflammation (Chapter 3).
Airway infection: Although infection is not thought to play a role in the initiation of tissue destruction, bacterial and/or viral infections cause acute exacerbations.
The idea that proteases are important is based in part on the observation that patients with a genetic deficiency of the anti-protease α1-anti-trypsin have a predisposition to develop pulmonary emphysema, which is compounded by smoking. About 1% of all patients with emphysema have this defect. α1-anti-trypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases (particularly elastase) secreted by neutrophils during inflammation. α1-anti-trypsin is encoded by a gene in the proteinase inhibitor (Pi) locus on chromosome 14. The Pi locus is polymorphic, and approximately 0.012% of the U.S. population is homozygous for the Z allele, a genotype that is associated with markedly decreased serum levels of α1-anti-trypsin. More than 80% of these individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and is of greater severity if the individual smokes.
Protease-mediated damage of extracellular matrix has a central role in the airway obstruction seen in emphysema. Small airways are normally held open by the elastic recoil of the lung parenchyma, and the loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles reduces radial traction and thus causes the respiratory bronchioles to collapse during expiration. This leads to functional airflow obstruction despite the absence of mechanical obstruction.
MORPHOLOGYThediagnosisandclassificationofemphysemadependlargelyonthemacroscopicappearanceofthelung.Typicalpanacinar emphysema producespale,voluminouslungsthatoftenobscuretheheartwhentheanteriorchestwallisremovedatautopsy.Themacroscopicfeaturesofcentriacinar emphysema arelessimpressive.Untillatestages,thelungsareadeeperpinkthaninpanacinaremphysemaandlessvoluminous,andtheuppertwo-thirdsofthelungsaremoreseverelyaffectedthanthelowerlungs.Histologicexaminationrevealsdestruction of alveolar walls without fibrosis, leading to enlarged air spaces (