Sarcoidosis of the lungs: causes and pathogenesis

Causes of sarcoidosis of the lungs

The causes of sarcoidosis are unknown. For a long time, there was a perception that sarcoidosis is a peculiar form of tuberculosis and, consequently, is caused by mycobacteria of tuberculosis. However, at the present time this point of view is unpopular, it is held only by individual researchers. Against the tubercular nature of sarcoidosis are three important factors - negative tuberculin reactions in the majority of patients with sarcoidosis, the lack of the effect of treatment with anti-tuberculosis drugs and the high effectiveness of treatment with glucocorticoid drugs.

However, it is possible that in some cases sarcoidosis is caused by unusual, altered mycobacteria, as evidenced by the similarity of sarcoid and tuberculosis granulomas, as well as the detection of very small forms of mycobacteria in many patients with sarcoidosis.

Currently, the role of the following possible etiological factors of sarcoidosis is considered: yersiniosis, viral and bacterial infection, fungi, parasitic invasion, pine pollen, beryllium, zirconium, certain medications (sulfonamides, cytostatics).

The most common assumption is the polytheological genesis of the disease. The congenital predisposition to sarcoidosis is not excluded (family forms of sarcoidosis are described, as well as more often the detection of antigens HLA-A1, B8, B13 in patients with sarcoidosis in comparison with the general population).

[1], [2], [3], [4], [5]

Pathogenesis of pulmonary sarcoidosis

Currently, sarcoidosis is considered as a primary immune disease that occurs in response to an unknown etiologic factor and is characterized by the development of the alveolitis, the formation of granulomas, which can be fibrous or resorbed.

To a certain extent, the pathogenesis of sarcoidosis is similar to the pathogenesis of idiopathic fibrosing alveolitis.

In response to the effect of the etiologic factor, the initial stage of the disease develops - congestion in alveoli, interstitial lung tissue of alveolar macrophages and immunocompetent cells. A huge role belongs to alveolar macrophages. Their functional activity is dramatically increasing. Alveolar macrophages hyperproduce a number of biologically active substances:

• interleukin-1 (stimulates T-lymphocytes and attracts them to the inflammatory focus, ie interstitial lung tissue and alveoli);
• plasminogen activator;
• fibronectin (contributes to an increase in the number of fibroblasts, enhance their biological activity);
• mediators, stimulating the activity of monocytes, lymphoblasts, fibroblasts, B-lymphocytes (for more details, see "Idiopathic fibrosing alveolitis").

As a result of activation of alveolar macrophages, there is accumulation of lymphocytes, fibroblasts, monocytes, and also significantly activate T-lymphocytes. Activated T-lymphocytes secrete interleukin-2, under the influence of which T-effector lymphocytes are activated and produce a number of lymphokines. Along with this, T-lymphocytes, like alveolar macrophages, produce a number of substances that stimulate the proliferation of fibroblasts and, consequently, the development of fibrosis.

Due to the development of these cell relationships, the first morphological stage of the disease develops-lymphoid macrophage infiltration of the affected organ (in the lung tissue is the development of the alveolitis). Then, under the influence of mediators produced by activated T-lymphocytes and macrophages, epithelioid-cell granulomas occur. They can form in various organs: lymph nodes, liver, spleen, salivary glands, eyes, heart, skin, muscles, bones, intestines, central and peripheral nervous system, lungs. The most frequent localization of granulomas is the intrathoracic lymph nodes and lungs.

Granulomas have the following structure. The central part of the granuloma consists of epithelioid and giant multinucleated Pirogov-Langengans cells, they can be formed from monocytes and macrophages under the influence of activated lymphocytes. On the periphery of the granuloma are lymphocytes, macrophages, plasma cells, fibroblasts.

Granulomas in sarcoidosis are similar to tuberculosis granulomas, but unlike the latter they are not characterized by caseous necrosis, however, in some sarcoid granulomas, signs of fibrinoid necrosis can be observed.

A number of biologically active substances are produced in granulomas. In 1975, Liebermann found that granulomas in sarcoidosis produce an angiotensin-converting enzyme. It is produced by the endothelium of the lung vessels, as well as by alveolar macrophages and epithelioid cells of sarcoid granuloma. It was found that a high level of angiotensin-converting enzyme correlates with a high activity of the pathological process in sarcoidosis. It is possible that the production of angiotensin-converting enzyme granuloma by cells plays a role in the formation of fibrosis. A high level of angiotensin-converting enzyme leads to increased formation of angiotensin II, which stimulates fibrosing processes. It was found that sarcoidosis granulomas also produce lysozyme, which correlates with the activity of the pathological process and the production of angiotensin-converting enzyme.

In sarcoidosis, calcium metabolism is also impaired, which is manifested by gapercalcemia, calcaria, calcium deposition and calcification in the kidneys, lymph nodes, tissues of the lower extremities and other organs. It is assumed that the increased production of vitamin D is important in the development of hypercalcemia, in which alveolar macrophages and granuloma cells take part. In granulomas, the activity of alkaline phosphatase is also increased, usually before the fibrosing stage of the granuloma.

Sarcoid granulomas are located mainly in subpleural, perivascular, peribronchial parts of the lungs, in interstitial tissue.

Granulomas can completely dissolve or be fibrotic, which leads to the development of diffuse interstitial pulmonary fibrosis (stage III of sarcoidosis of the lungs) with the formation of a "cellular lung". The development of interstitial lung fibrosis is observed in 5-10% of patients, but Basset (1986) found the development of fibrosis in 20-28% of cases.

Granulomas that develop in sarcoidosis need to be differentiated from granulomas in exogenous allergic alveolitis.

The lack of transformation of the granulomatous stage into fibrosis can be explained by increased production of alveolar macrophages and lymphocytes of factors inhibiting the growth of fibroblasts and fibrosing.