COPD is a complex condition that has only recently been studied on the molecular level. Although ~95% of COPD is thought to be caused by cigarette smoke, the exact cause-and-effect nature of the pathophysiology of COPD is not well-understood. Nonetheless, several correlations have been drawn, and several “pieces of the puzzle” have been studied fruitfully.
Genetic Causes: Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin (A1AT or AAT) is a serpin and plays an important role in keeping serine proteases such as neutrophil elastase in check during inflammation in order to minimize damage to lung tissue. Mutations in the SERPINA1 gene causes A1AT deficiency or a nonfunctional form of A1AT. The Z variant of this gene is the most common, and yields the Z variant of the A1AT protein, with a Glu342Lys mutation (Jezierski 2001).
The wild-type M variant A1AT protein has a reactive loop that is responsible for proteinase inhibition. The mobility of this loop is controlled by electrostatic interactions between the side chains of Glu342 and Lys290, which are located at the junction of the reactive loop and a beta sheet. The Glu342Lys mutation (“the Z mutation”) introduces instabilities in the reactive loop region, decreasing its efficacy as a protease inhibitor (Jezierski 2001). The effect of this mutation on the structure of A1AT is shown in Figure 5.
Reactive Oxygen Species
Reactive Oxygen Species (ROS) are produced by inflammatory cells. Although the production of ROS is a potent defense mechanism, it can also cause damage to lipids, proteins, and DNA, which is thought to be correlated to lung tissue damage in COPD cases.
ROS can react with arachidonic acid to form 4-hydroxynonenal (4-HNE), an α,β-unsaturated hydroxyalkenal, which plays a key role in signal transduction in a variety of pathways. In a 2012 study by Takimoto et al, it was found that exposure of mice lungs to 4-HNE induced the accumulation of inflammatory cells, “enlarged the airspace, and induced goblet cell metaplasia [replacement of differentiated cells] of the airways”, which are characteristic COPD physiology (Takimoto 2012). Structures are shown in Figure 6.
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, which is involved in cellular responses to various stress stimuli. Although it has many functions and is involved in many processes, cytokine production is its primary relevance to COPD. ROS activate NF-κB, which further amplifies the inflammatory response. The exact pathway of this activation is unknown, but there are several redox-sensitive steps in the activation pathway that are known (Barnes 2003). Because inflammatory cells can release ROS, there is potential for positive-feedback in this process, which can yield significant damage to lung parenchyma due to ROS and elastase activity.
There is increased macrophage expression of matrix metalloproteinase 1 (MMP-1, collagenase) and MMP-9 (gelatinase B) in COPD patients. In a 1997 experiment, it was demonstrated that emphysema induced by chronic cigarette exposure is prevented in MMP-12-/- mice (Hautamaki 1997) and in two 2000 studies, it was shown that in MMP12-/- mice, emphysema induced by interleukin 13 (IL-13) and interferon- γ (IFN- γ) overexpression is reduced, as well as a reduction of recruitment of monocytes into the lung. It is speculated that MMPs activate the latent form of TGF‐β (transforming growth factor beta, a cytokine), resulting in the recruitment of monocytes (Barnes 2003). This possible mechanism of action is shown in Figure 7.
The structure of MMP-12 has been resolved (Nar 2001), and its mechanistic activity has been elucidated. The protein binds a zinc ion and three calcium ions, and has an N-terminus proenzyme domain that is cleaved, activating TGF‐β.
Cigarette smoke has been shown to impair the activity of HDAC (histone deacetylase) in macrophages, which has been correlated to amplification of the expression of inflammatory genes (Barnes 2003).
Summary of Molecular Basis
The inflammatory response, when uncontrolled, leads to the pathophysiology of COPD. Neutrophils release elastase as part of the inflammatory response, which can damage lung tissue to great extents if the individual is A1AT-deficient. ROS can affect several types of biomolecules; one such target is arachidonic acid, which can be converted to 4-HNE, which can induce the recruitment of inflammatory cells. Matrix metalloproteases, similarly, activate TGF- β to recruit monocytes, which can damage lung parenchyma. Lastly, cigarette smoking can affect the activity of HDAC, and amplify the expression of inflammatory genes in an epigenetic fashion.