FIGURE 9.7 Appearance of honeycomb lung from patient with severe pulmonary
fibrosis. Many cystic areas are seen between bands of extensively scarred and
retracted pulmonary parenchyma.
Pathogenesis
Much research during the past 2 decades has attempted to clarify the pathogenetic sequence of events in various types of diffuse parenchymal lung disease. However, in most cases the factors that initiate and propagate these diseases remain unknown, and our understanding of the cellular and biochemical events producing inflammation and fibrosis remains mostly at the descriptive level. More recently, there has been greater interest in the potential role of genetic factors in development of some of the diffuse parenchymal lung diseases, either as a primary determinant or as an important modifier of the patient’s response to a potentially injurious exposure. Some gene variants of particular interest have been ones involved in coding for mucins (especially MUC5B), surfactant proteins A and C, and telomerase components.
This section outlines the general scheme of events thought to be operative in the production of parenchymal inflammation and fibrosis. Chapters 10 and 11 discuss specific diseases and provide additional information believed to be relevant to the pathogenesis of each disease. The general scheme outlined here has features similar to that of other forms of lung injury described elsewhere in this book (e.g., emphysema in Chapter 6 and ARDS in Chapter 29). A fundamental but unanswered question is what determines whether an injurious agent eventually leads to emphysema, acute lung injury (with ARDS), or chronic parenchymal inflammation and fibrosis.
Fig. 9.8 summarizes the general sequence of events presumed to be common to many of the diffuse parenchymal lung diseases. The events can be divided into three stages: initiation, propagation, and final pathologic consequences. Each of these stages is considered in turn.
FIGURE 9.8 Schematic diagram illustrating general aspects of pathogenesis of
diffuse parenchymal lung diseases.
Pathogenetic features of diffuse parenchymal lung disease are as follows:
1.Initiation—by antigens, toxins
2.Propagation—with inflammatory cells, proteases, cytokines
3.Final pathologic consequence—fibrosis
The initiating stimulus for the diffuse parenchymal lung diseases is generally believed to be either a toxin or an antigen. The most obvious presumed toxins include some of the inhaled inorganic particles (e.g., asbestos) responsible for producing the pneumoconioses. Smoking also appears to be an important factor for development of the smoking-related interstitial pneumonias (RB-ILD and DIP) as well as pulmonary Langerhans cell histiocytosis (eosinophilic granuloma, discussed in Chapter 11), and is a risk factor for IPF. Inhaled antigens have been best identified as the cause of hypersensitivity pneumonitis. In sarcoidosis and perhaps in IPF, exposure to one or more antigens may initiate the disease, but no specific antigens have been identified.
After exposure to an initiating stimulus occurs, a complex series of interrelated events is responsible for propagation of the disease. At the microscopic level, the consequence of these propagating events is inflammation, a hallmark of many but not all of the diffuse parenchymal lung diseases. Toxins may be directly injurious to pulmonary parenchymal (alveolar epithelial) cells, whereas either toxins or antigens may result in activation and recruitment of inflammatory and immune cells. Inflammatory cells can release a variety of mediators (e.g., proteolytic enzymes, toxic oxygen radicals) that can secondarily further injure
pulmonary parenchymal cells. In addition, a wide variety of cytokine mediators produced by epithelial,
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inflammatory, and immune cells have been identified. These cytokines have complex secondary effects on other inflammatory and immune cells, often acting either to amplify or diminish the inflammatory response.
Some cytokines (e.g., transforming growth factor [TGF]-β and platelet-derived growth factor) are capable of recruiting and stimulating replication of fibroblasts, which are critical for the eventual production of new connective tissue. Action of proteases from inflammatory cells may also be responsible for degradation of connective tissue components. The combination of new synthesis and degradation of connective tissue defines the derangement of the connective tissue matrix that is seen histologically as fibrosis, the final pathologic consequence of diffuse parenchymal lung disease. In IPF, the most recent (and now prevailing) concept is that alveolar epithelial injury results in epithelial cell expression of cytokine mediators that promote fibrosis, and that inflammation, although present in variable degrees, is not the critical trigger for the development of fibrosis.
Pathophysiology
With minor exceptions and variations, the pathophysiologic features of the chronic diffuse parenchymal lung diseases are similar and therefore are discussed here as a single group. As a result of the inflammation and fibrosis affecting the alveolar walls, the following abnormalities are generally seen (Fig. 9.9): (1) decreased compliance (increased stiffness) of the lung, (2) generalized decrease in lung volumes, (3) loss of alveolar-capillary surface area resulting in impaired diffusing capacity, (4) abnormalities in small airway function without generalized airflow obstruction, (5) disturbances in gas exchange, usually consisting of hypoxemia without CO2 retention, and (6) in some cases, pulmonary hypertension. Each of these features is briefly considered in turn.
FIGURE 9.9 Schematic diagram illustrating interrelationships between various
pathologic and physiologic features of diffuse parenchymal lung disease.
Decreased compliance
Lung distensibility is significantly altered by processes involving inflammation and fibrosis of the alveolar walls. The lungs become much stiffer, have greatly increased elastic recoil, and therefore require greater distending (transpulmonary) pressures to achieve any given lung volume. The pressure-volume or compliance curve is shifted to the right (see Fig. 8.3), and at any given lung volume, a much higher elastic
recoil pressure is found than in normal lungs. Because wider swings in transpulmonary pressure are required to achieve a normal tidal volume during inspiration, the patient’s work of breathing is increased. As a result, patients with diffuse parenchymal lung disease tend to breathe with smaller tidal volumes but increased respiratory frequency. This method allows the patient to expend less energy per breath but maintain adequate alveolar ventilation.
Compliance curves in diffuse parenchymal lung disease are shifted downward and to the right, reflecting increased stiffness of the lung.
Decrease in lung volumes
Early in the course of diffuse parenchymal lung disease, lung volumes may be normal. However, in most cases, some reduction in lung volumes is seen shortly thereafter, including a reduction in total lung capacity (TLC), vital capacity (VC), functional residual capacity (FRC), and, to a lesser extent, residual volume (RV). The decreases in TLC, FRC, and RV are direct consequences of the change in lung compliance. At TLC, the force generated by the inspiratory muscles is balanced by the inward elastic recoil of the lung. Because the recoil pressure is increased, this balance is achieved at a lower lung volume or lower TLC. At FRC, the outward recoil of the chest wall is balanced by the inward elastic recoil of the lung. This balance is achieved at a lower lung volume or lower FRC because of the greater elastic recoil of the lung. As discussed in Chapter 1, RV is primarily determined by the strength of the expiratory muscles, but a small component is determined by the inward elastic recoil of the lungs. Because the elastic recoil is greater in diffuse parenchymal lung disease, the RV is slightly smaller. In general, TLC is reduced more than RV, so it follows that VC (representing the difference between TLC and RV) is also decreased.
Lung volumes are characteristically decreased in diffuse parenchymal lung disease.
Impairment of diffusion
Measurement of diffusion by the usual techniques involving carbon monoxide typically shows a decrease in diffusing capacity. Although thickening of the alveolar-capillary interface (due to interstitial inflammation and fibrosis) might be expected to be responsible for this decrease, in fact it is not the major factor. Rather, the processes of inflammation and fibrosis destroy a portion of the alveolar-capillary interface and reduce the surface area available for gas exchange. This decrease in surface area is the primary mechanism responsible for the observed diffusion abnormality.
Diffusing capacity is reduced, with destruction of a portion of the alveolar-capillary interface and reduced surface area for gas exchange.
Abnormalities in small airway function
Large airways generally function normally in these patients, and the forced expiratory volume in 1 second to forced vital capacity ratio (FEV1/FVC) is usually normal or even increased. However, frequently the pathologic process occurring in the alveolar walls also affects small airways within the lung. Light microscopy commonly demonstrates inflammation and fibrosis in the peribronchiolar regions, with narrowing of the lumen of the small airways or bronchioles. Tests of small airway function often show the physiologic effects of this narrowing. The clinical importance of small airway dysfunction in the absence
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of larger airway abnormalities is uncertain, but it is likely that ventilation-perfusion ( 
) mismatching and hypoxemia are consequences. Evidence of more significant airflow obstruction may be seen in a few disorders causing diffuse parenchymal lung disease. This relatively infrequent problem sometimes results from severe fibrosis and airway distortion.
Small airway function is often disturbed in diffuse parenchymal lung disease. Large airway function is generally preserved.
Disturbances in gas exchange
The gas exchange consequences of diffuse parenchymal lung disease most frequently consist of hypoxemia without CO2 retention, and in fact hypocapnia typically is present. The pathologic process in the alveolar
walls is uneven, and normal matching of ventilation and perfusion is disrupted. As a result, 
mismatch is the primary factor contributing to hypoxemia. In patients with small airway disease,
dysfunction at this level probably also contributes to 
mismatch and hypoxemia. Characteristically, patients with diffuse parenchymal lung disease become even more hypoxemic with exercise. Again, the
primary mechanism of oxygen desaturation associated with exertion is worsening 
mismatch, but diffusion limitation may also be a contributing factor, particularly with higher levels of exercise and with exercise performed at higher altitudes. The combination of impaired diffusion and decreased transit time of the red blood cell during exercise may prevent complete equilibration of PO2 in pulmonary capillary blood with alveolar PO2. Despite the often profound hypoxemia in patients with severe pulmonary fibrosis, PCO2 is usually normal or low because patients are able to increase minute ventilation sufficiently to compensate for a decrease in tidal volume and for any additional dead space. Elevation of PCO2 does not generally occur until the very late stages of the disease.
Arterial blood gases in diffuse parenchymal lung disease generally show hypoxemia (due to 
mismatch) and normal or decreased PCO2. PO2 falls even further with exercise.
Pulmonary hypertension
Eventually, patients with severe diffuse parenchymal lung disease may develop some degree of pulmonary hypertension. Typically, the two main contributing factors are (1) hypoxemia and (2) obliteration of small pulmonary vessels by the fibrotic process within the alveolar walls. During exercise, pulmonary hypertension becomes more marked; this is due partly to worsening hypoxemia and partly to limited ability of the pulmonary capillary bed to recruit new vessels and normally distend to accommodate the increase in cardiac output associated with exercise. Importantly, however, a subset of patients with diffuse parenchymal lung diseases will develop more severe pulmonary hypertension, and the pulmonary vascular changes are similar to those in patients with idiopathic pulmonary arterial hypertension (see Chapter 14). In these patients, the pulmonary hypertension is due to a primary process affecting pulmonary vessels in addition to the destruction and fibrosis of alveolar walls. Notably, the level of pulmonary hypertension does not correlate well with the degree of fibrosis in patients with diffuse parenchymal lung diseases but is independently associated with a worse prognosis. Thus, although there is a clear association between pulmonary hypertension and diffuse parenchymal lung diseases, the exact pathophysiologic and clinical relationships are not fully elucidated.