The Potential Role of Cigarette Smoke, Elastic Fibers, and Secondary Lung Injury in the Transition of Pulmonary Emphysema to Combined Pulmonary Fibrosis and Emphysema

Abstract

Combined pulmonary fibrosis and emphysema (CPFE) is a distinct syndrome associated with heavy smoking. The fibrotic component of the disease is generally believed to be superimposed on previously existing pulmonary emphysema, but the mechanisms responsible for these changes remain poorly understood. To better understand the pathogenesis of CPFE, we performed a series of experiments that focused on the relationships between lung elastic fibers, cigarette smoke, and secondary lung injury. The results indicate that even brief smoke exposure predisposes the lung to additional forms of lung injury that may cause alveolar wall fibrosis. The proinflammatory activity of smoke-induced structural alterations in elastic fibers may contribute to this process by enhancing secondary lung inflammation, including acute exacerbations of chronic obstructive pulmonary disease. Furthermore, the levels of the unique elastin crosslinks, desmosine and isodesmosine, in blood, urine, and sputum may serve as biomarkers for the transition from pulmonary emphysema to interstitial fibrosis. While the long-term effects of these inflammatory reactions were not examined, the current studies provide insight into the potential relationships between elastic fiber injury, cigarette smoke, and secondary lung injury. Determining the mechanisms involved in combined pulmonary emphysema and fibrosis and developing a sensitive biomarker for this type of lung injury may permit timely therapeutic intervention that could mitigate the high risk of respiratory failure associated with this condition.

Keywords: cigarette smoke; desmosine; elastin; lipopolysaccharide; pulmonary emphysema; pulmonary fibrosis.

Figure 1

(Left) The development of pulmonary emphysema involves a loss of structurally intact elastic fibers (bold lines). The mechanism responsible for this change involves enzymatic and oxidative degradation of the fibers, which increases the mechanical strain on alveolar walls, resulting in their distention and rupture. (Right) Photomicrograph of postmortem lung from a smoker with moderate pulmonary emphysema showing fragmentation of elastic fibers (arrows). Reprinted with permission [21]. Original magnification: 1000×.

Figure 2

Total lung DID was increased at two months, then markedly decreased over the next four months before undergoing a secondary increase over the remaining course of the study [22]. N ≥ 3 for each group. T-bars indicate the standard error of the mean (SEM). The number of asterisks above the bars correlates with the level of statistical significance (p < 0.05, p < 0.01).

Figure 3

The decrease in total lung DID content shown in Figure 2 is reflected by relatively high levels of BALF DID, whereas the subsequent increase in lung DID is associated with a marked decline in BALF DID 22]. N ≥ 3 for each group. T-bars indicate SEM.

Figure 4

The intratracheal administration of elastase before the instillation of LPS results in a significantly higher level of BALF leukocytes than the other treatment groups [6]. The numbers above the bars indicate N. T-bars denote SEM. Reprinted with permission.

Figure 5

The intratracheal administration of elastase prior to the instillation of LPS results in a significantly higher level of BALF neutrophils compared to the other treatment groups [6]. The numbers above the bars indicate N. T-bars denote SEM. Reprinted with permission.

Figure 6

The combination of elastin peptides and LPS had a significantly greater chemoattractive effect on BALF macrophages compared to the other treatment groups [6]. Chemotattraction was measured by labeling cells with a fluorescent dye. The numbers above the bars indicate N. T-bars denote SEM. Reprinted with permission.

Figure 7

The intratracheal administration of elastase prior to the instillation of LPS results in a significantly greater elastic fiber surface area compared to treatment with LPS alone, consistent with increased proinflammatory structural alterations in these fibers [6]. The numbers above the bars indicate N. T-bars denote SEM. Reprinted with permission.

Figure 8

Exposure to cigarette smoke prior to intratracheal instillation of Amiodarone (upper graph) results in a significantly greater influx of neutrophils into the lung compared to post-treatment with smoke (lower graph) [33]. N = 3 for each group. T-bars indicate SEM. Reprinted with permission.

Figure 9

Exposure to cigarette smoke prior to intratracheal instillation of LPS (upper graph) results in a significantly greater influx of neutrophils into the lung compared to post-treatment with smoke (lower graph) [43]. N = 5 for each group. T-bars indicate SEM. Reprinted with permission.

Figure 10

Diagram of the proposed mechanisms involved in the pathogenesis of CPFE.