4.1: Basis of Restrictive Lung Disease

The restrictive lung diseases are characterized by pathophysiological disruption of the lung interstitial tissue that causes problems with lung expansion. As such, these diseases are more specifically referred to as the interstitial lung diseases, or ILDs. There are about 150 conditions that disrupt lung structure and generally produce a restrictive, rather than obstructive, disorder.

This section provides a broad overview and generalized mechanisms of interstitial lung disease. Subclassifications and details of specific conditions are presented in the next section.

Before we start taking about diseases affecting the lung interstitium, let us remind ourselves of what it is.

The interstitial tissue, sometimes referred to as parenchyma, surrounds the alveolar and capillary structures and contributes to the mechanical behavior of the lungs. The interstitium is extremely thin between the alveoli and capillaries, and forms the basement membrane through which gas exchange occurs. On the parenchymal side of the capillaries the interstitium is more substantial and is more involved in fluid exchange. There is also substantial amounts of interstitial tissue in the spaces around major vessels and airways, and it also makes up the interlobular septa.

Mechanisms of ILD

Now we will look at the generalized mechanism of interstitial lung disease (figure 4.1). It is worth noting that the numerous conditions that the term ILD encompasses have subtle differences in mechanism and manifestations, and these differences are what we will deal with elsewhere.

Generally though, ILD starts with an initial insult to the lung (#1, figure 4.1); the type of insult is a major contributor to the different ILD conditions. (It probably will not be what is depicted in figure 4.1, but if it was, it might lead to the inflammatory condition of tiefitis.)

There is then a response by neutrophils and alveolar macrophages (#2, figure 4.1). The macrophage response seems particularly important to the development of ILD. Release of cytokines (#3, figure 4.1) attracts other inflammatory cells, and the arrival of polymorphonuclear leukocytes and lymphocytes play an important role in disease instigation. These cells release cytokines, enzymes, and toxic oxygen radicals that damage and destroy local tissue. Released growth factors, such as TGF-Beta, instigate the transition of mesenchymal cells to fibroblasts.

It is worth noting at this point that some forms of ILD are caused by an exaggerated immune reaction—either through an allergic-like response, or a direct immune disorder.

The destruction of tissue and activity of a growing number of fibroblasts results in the inflamed interstitium becoming fibrosed with excess connective tissue, particularly collagen (#4, figure 4.1).

Figure 4.1: Basic mechanism of interstitial lung disease.

Pathology of ILD

These changes in structure dramatically change the functional and mechanical properties of the tissue. The changes also tend to follow a characteristic pattern, although, as you might imagine, different conditions have subtle differences in pattern.

The action of fibroblasts laying down connective tissue, combined with the destruction of alveolar and capillary structures, leads to a widening of airspaces with thick collagenous and infiltrated walls (figure 4.2A and 4.2B), which are a functionally significant departure from the ideal structure for gas exchange.

The thickened basement membrane poses a significant obstacle to the transfer of gases, and the dense connective tissue stiffens the lung and thereby reduces its compliance. Combined with loss of capillary beds and airspace surface area, gas exchange is reduced.

At the end of the disease the lung takes on a characteristic honeycomb appearance, and "ground glass opacities" are a hallmark sign on CT images (figure 4.2C). These morphological changes lead to pathophysiological consequences that are shared by most forms of the disease, as all cause varying degrees of interstitial inflammation and connective tissue deposition.

Figure 4.2: Changes in pulmonary histology (A, B) and gross anatomy (C) with interstitial lung disease.

Pathophysiology of ILD

The first major issue is the reduced diffusion capacity of the involved areas, and all ILD patients demonstrate a reduced transfer factor, or DLCO (figure 4.3).

Because of the heterogenous distribution of the disease, and the involvement of the pulmonary circulation, severe V/Q abnormalities arise throughout the lung. This and the reduced diffusion capacity result in hypoxemia. In the chronic disease state this may lead to cor pulmonale (figure 4.3).

The reduction in lung compliance leads to a reduced lung volume. This is easily detected with spirometry as shown by the inner plot of the flow-volume loop in figure 4.3. Because FEV₁ and FVC are both reduced, the ratio frequently remains the same or may even rise; as such FEV₁/FVC is a poor indicator of restrictive disease.

Figure 4.3: Pathophysiological consequences of ILD.

The reduced lung volume and compliance results in a characteristic rapid, shallow breathing pattern as the patient tries to maintain alveolar ventilation (figure 4.3). However, while avoiding unnecessary increases in the work of breathing by not trying to over-expand the noncompliant lung, the rapid shallow breathing proportionally increases dead space ventilation.

The reduction in tidal volume, combined with a raised hypoxic drive to breathe, results in the cardinal symptom of ILD, which is dyspnea (figure 4.3).

Clinical Signs of ILD

The correlation of dyspnea and disease stage is closer in ILD than any other respiratory disease. The onset is insidious, appearing first during exercise, and it likely contributes to the other major complaints of weakness and fatigue. The dyspnea gets progressively worse until it can be debilitating.

Inflammation and excitation of pulmonary receptors leads to a nonproductive and persistent cough, and upon examination patients will have limited chest expansion and demonstrate the characteristic breathing pattern of restrictive lung disease.

Hallmark lung sounds are fine crackles, commonly found at the base of the lung, and may appear louder than expected because of increased transmission through denser than normal tissue.

At later stages of the disease the patient shows signs of the prolonged hypoxemia with digital clubbing and cyanosis.