Emphysema

Overview

Emphysema is a morphologically-defined entity characterized by permanent enlargement of airspaces distal to the terminal bronchiole, that is the respiratory acinus. Emphysema prototypically results in an irreversible obstructive pattern of pulmonary function and is considered a component of COPD. Below we discuss the etiology and morphology of emphysema and refer the patient to the COPD page for a discussion of the clinical consequences of this disease which often occurs together with chronic bronchitis.

Morphology

Although emphysema is defined as enlargement of the respiratory acinus, the pattern of enlargement may not be uniform and can take on one of three basic forms. Importantly, different etiologies of emphysema tend to produce different patterns of acinar enlargement and thus the morphology of emphysema can provide a clue as to the cause.

Airspace enlargement in centriacinar emphysema tends to focus on the respiratory bronchiole and largely spares the distal alveoli and alveolar ducts. Centriacinar emphysema is typically observed in smokers and is infrequently seen in those with Alpha-1 Antitrypsin Deficiency.

Airspace enlargement in panacinar emphysema affects the entire respiratory acinus, leading to dilation of the respiratory bronchiole]s and destruction of alveolar septa. This pattern of emphysema is typically observed in those with Alpha-1 Antitrypsin Deficiency and less commonly in smokers.

Etiology

Emphysema is most often observed in two patient populations: Long-time smokers and those with Alpha-1 Antitrypsin Deficiency. Although seemingly quite different insults, smoking and deficiency of Alpha-1 Antitrypsin likely lead to emphysematous morphological changes to the lung via the same basic mechanism. Currently, it is thought that in a healthy lung there is a delicate balance between neutrophil-derived proteases and circulating anti-proteases. Smoking and alpha-1 antitrypsin deficiency appear to derange this delicate balance, leading to uncontrolled proteolytic destruction and thus weakening of the pulmonary substance. We discuss this "Protease-Antiprotease Hypothesis" in more detail below and then detail how smoking and deficiency of alpha-1 antitrypsin can lead to derangement of the protease-antiprotease balance.

Even in a healthy lung, neutrophils continuously extravasate into the lung parenchyma at a low level and release granules of proteases which digest the elastin-rich pulmonary extracellular matrix. Counteracting the digestive action of these neutrophil-derived proteases are a variety of soluble antiproteases, such as alpha-1 antiprotease, that are delivered to the lung parenchyma by the circulation. In a healthy lung, proteases are successfully inhibited by circulating antiproteases and pulmonary tissue destruction is averted. The Protease-Antiprotease Hypothesis posits that this delicate balance between nutrophil-derived proteases and circulating antiproteases is disrupted by smoking or alpha-1 antiprotease deficiency.

Alpha-1 antitrypsin is an important circulating antiprotease that specifically inhibits elastase, a neutrophil protease that digests elastin. The alpha-1 antitrypsin gene can be expressed from a variety of genetic alleles which produce different levels of the protein. The Z allele results in very low levels of alpha-1 antitrypsin synthesis and in individuals homozygous for the Z allele, notated as PiZZ, display very low levels of circulating alpha-1 antitrypsin activity. Consequently, neutrophil elastase can digest pulmonary tissue largely unchecked in PiZZ individuals, leading to progressive destruction of the respiratory acinus and a picture of emphysema.

Long-term and frequent exposure of the respiratory acinus to cigarette smoke appears to tip the balance in favor of neutrophil proteases in a number of ways. First, smoking appears to result in alveolar inflammation, thus enhancing the number of neutrophils and macrophages that subsequently release elastase. Secondly, inhaled cigarette smoke contains a large number of reactive oxygen species that appear to inactivate alpha-1 antitrypsin deficiency. Consequently, smoking not only increases the total amount of released proteases but also inactivates perfusion-delivered anti-proteases, thus tipping the balance toward progressive parenchymal destruction that ultimately yields a morphological picture of emphysema.

Sequelae

Progressive destruction of the lung extracellular matrix yields enlargement of the respiratory acinus which is the morphological hallmark of emphysema. However, this destruction also yields a number of other important functional derangements in the organ which contribute to the pathophysiological sequelae of emphysema.

As explained in lung compliance, the molecular basis for the elasticity and recoil of the lung is in part due to the combined action of the organ's elastin fibers. This elastic recoil maintains traction around small conducting airways and thus maintains their patency during expiration (See "Expiration" section of Airflow Resistance). Progressive and widespread destruction of the lung's elastin fibers seen in emphysema reduces the lung's elastic recoil with significant consequences for both expiratory airflow and total lung volume. The reduced elastic traction on the lung's small airways results in their collapse during expiration and thus yields a dynamic obstruction to airflow which can manifest as a obstructive pattern of pulmonary function (See: "Expiration" section of airflow resistance for fuller explanation). Additionally, the reduced total pulmonary elastic recoil can shift the balance between the opposing inward and outward forces of the lung and chest wall described in Integrated Pulmonary Compliance, yielding an increase in the lung's functional residual capacity that manifests as a significantly larger lung volume at rest.

Progressive destruction of respiratory acini observed in emphysema also results in widespread elimination of pulmonary capillaries. Over time, this can result in significant increases in the pulmonary vascular resistance.

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