Pulmonary Sarcoidosis - Causes and Pathogenesis

Causes of pulmonary sarcoidosis

The causes of sarcoidosis are unknown. For a long time, there was a concept that sarcoidosis was a specific form of tuberculosis and, therefore, was caused by Mycobacterium tuberculosis. However, at present, this point of view is unpopular and is held only by individual researchers. Three important circumstances argue against the tuberculous nature of sarcoidosis - negative tuberculin reactions in most patients with sarcoidosis, the lack of effect from treatment with anti-tuberculosis drugs, and the high efficiency 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 between sarcoid and tuberculous granuloma, 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 being considered: yersiniosis, viral and bacterial infections, fungi, parasitic invasion, pine pollen, beryllium, zirconium, and certain medications (sulfonamides, cytostatics).

The most common assumption is about the polyetiological genesis of the disease. Congenital predisposition to sarcoidosis is not excluded (familial forms of sarcoidosis have been described, as well as more frequent detection of HLA-A1, B8, B13 antigens in patients with sarcoidosis compared to the general population).

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Pathogenesis of pulmonary sarcoidosis

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

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

In response to the impact of the etiologic factor, the initial stage of the disease develops - accumulation of alveolar macrophages and immunocompetent cells in the alveoli, interstitial tissue of the lungs. Alveolar macrophages play a huge role. Their functional activity increases sharply. Alveolar macrophages hyperproduce a number of biologically active substances:

• interleukin-1 (stimulates T-lymphocytes and attracts them to the site of inflammation, i.e. the interstitial tissue of the lungs and alveoli);
• plasminogen activator;
• fibronectin (promotes an increase in the number of fibroblasts and enhances their biological activity);
• mediators that stimulate the activity of monocytes, lymphoblasts, fibroblasts, B-lymphocytes (for more details, see “Idiopathic fibrosing alveolitis”).

As a result of activation of alveolar macrophages, lymphocytes, fibroblasts, monocytes accumulate, and T-lymphocytes are significantly activated. 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.

As a result of the development of the above-mentioned cellular relationships, the first morphological stage of the disease develops - lymphoid-macrophage infiltration of the affected organ (in lung tissue - this is the development of alveolitis). Then, under the influence of mediators produced by activated T-lymphocytes and macrophages, epithelioid-cell granulomas arise. 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 common 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-Langenghans cells, they can form from monocytes and macrophages under the influence of activated lymphocytes. Lymphocytes, macrophages, plasma cells, and fibroblasts are located along the periphery of the granuloma.

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

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

In sarcoidosis, a calcium metabolism disorder has also been established, which manifests itself as hypercalcemia, calciuria, calcium deposition and the formation of calcifications in the kidneys, lymph nodes, tissues of the lower extremities and other organs. It is assumed that increased production of vitamin D, in which alveolar macrophages and granuloma cells participate, is important in the development of hypercalcemia. In granulomas, alkaline phosphatase activity is also increased, which usually precedes the fibrosis stage of the granuloma.

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

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

Granulomas developing in sarcoidosis must be differentiated from granulomas in exogenous allergic alveolitis.

The absence of transformation of the granulomatous stage into fibrosis can be explained by the increased production by alveolar macrophages and lymphocytes of factors that inhibit fibroblast growth and fibrosis formation.