Idiopathic fibrosing alveolitis - Causes and pathogenesis

Causes of idiopathic fibrosing alveolitis

The causes of idiopathic fibrosing alveolitis have not been definitively established. The following possible etiologic factors are currently under discussion:

• viral infection - the so-called latent, "slow" viruses, primarily the hepatitis C virus and the human immunodeficiency virus. A possible role of adenoviruses, Epstein-Barr virus is also assumed (Egan, 1995). There is a point of view on the dual role of viruses in the development of idiopathic fibrosing alveolitis - viruses are the primary triggers for the development of lung tissue damage and, in addition, virus replication occurs in already damaged tissue, which naturally contributes to the progression of the disease. It has also been established that viruses interact with genes regulating cell growth, and thus stimulate collagen production, fibroformation. Viruses are also capable of intensifying existing chronic inflammation;
• environmental and professional factors - there is evidence of a connection between idiopathic fibrosing alveolitis and long-term professional contact with metal and wood dust, brass, lead, steel, and some types of inorganic dust - asbestos, silicate. The etiological role of aggressive etiological factors is not excluded. However, it should be emphasized that the above-mentioned professional factors cause pneumoconiosis, and in relation to idiopathic fibrosing alveolitis, they can probably be considered as trigger factors;
• genetic predisposition - the role of this factor is confirmed by the presence of familial forms of the disease. It is assumed that the basis of genetic predisposition to idiopathic fibrosing alveolitis is hereditary polymorphism of genes encoding proteins involved in the processing and presentation of antigens to T-lymphocytes. In recent years, a large role in the development of idiopathic fibrosing alveolitis has been attributed to a genetic defect - a deficiency of a1-antitrypsin (this contributes to the destruction of interalveolar septa, interstitial tissue, the development of pulmonary emphysema) and a decrease in the T-suppressor function of T-lymphocytes (this favors the development of autoimmune reactions).

Pathogenesis of idiopathic fibrosing alveolitis

The main pathological processes occurring in idiopathic fibrosing alveolitis are diffuse inflammation of the interstitial tissue of the lungs and the subsequent development of an intense widespread fibrotic process.

The pulmonary interstitial tissue is the connective tissue matrix of the alveolar wall, consisting mainly of type I collagen and surrounded by epithelial and endothelial basement membranes. The alveolar walls are common to two adjacent alveoli, the alveolar epithelium covers the wall on both sides. Between the two sheets of epithelial lining is the interstitium, which contains bundles of collagen, reticular and elastic fibers, as well as cells - histiocytes, lymphocytes, neutrophils, fibroblasts and a network of blood capillaries. The alveolar epithelium and capillary endothelium lie on the basement membrane.

Currently, the following main pathogenetic factors of idiopathic fibrosing alveolitis are known.

Development of persistent autoimmune processes in the pulmonary interstitium

Under the influence of an unknown etiological factor, antigens are expressed on the cell membranes of the alveoli and interstitial tissue of the lungs. The following may act as autoantigens:

• a protein of lung tissue weighing 70-90 kDa. It is localized on the epithelial cells of the alveoli, in particular on type 2 alveolocytes;
• native collagen.

Antibodies are produced against autoantigens. In 80% of patients with idiopathic fibrosing alveolitis, autoantibodies to lung tissue protein and collagen types I, II, III and IV are detected in the blood. Then immune complexes are formed in the lungs (autoantigens + autoantibodies), an immune-inflammatory process develops in the pulmonary interstitium, acquiring a persistent course.

Proliferation and activation of alveolar macrophages

Currently, the alveolar macrophage is considered the central inflammatory cell. Alveolar macrophages are activated by immune complexes and play the following role in the development of idiopathic fibrosing alveolitis;

• actively participate in the development of the inflammatory process in the interstitial tissue of the lungs, producing interleukin-1 and chemoattractants for neutrophilic leukocytes, causing their accumulation and increased activity, and also releasing leukotriene B4, which has a pronounced pro-inflammatory effect;
• promote the growth and proliferation of fibroblasts and other mesenchymal cells, the development of fibrosis in the interstitial tissue of the lungs. Alveolar macrophages secrete growth factors (platelet, insulin-like growth factor, transforming growth factor), as well as fibronectin. Under the influence of growth factors, activation and proliferation of fibroblasts occurs, fibronectin has a chemotactic effect on fibroblasts. Activated fibroblasts intensively synthesize matrix collagen, elastin, an inhibitor of proteolytic enzymes and, thus, cause the development of fibrosis;
• release oxygen radicals that have a damaging effect on the lung parenchyma.

Activation and proliferation of neutrophils, eosinophils, mast cells

In addition to the activation of alveolar macrophages, there is activation and proliferation of other cells that play an important role in the pathogenesis of IFA:

• activation of neutrophilic leukocytes - neutrophils accumulate in the alveolar septa, directly in the alveoli themselves, they are considered the main effector cells in idiopathic fibrosing alveolitis. Neutrophils release a number of damaging factors - proteases (collagenase, elastase), oxygen radicals;
• activation of eosinophils - accompanied by the release of a number of substances that have a pro-inflammatory and damaging effect (leukotrienes, proteases, oxygen radicals, eosinophil cationic protein, large basic protein, etc.);
• accumulation and activation of mast cells - in areas of fibrosis, the number of mast cells is sharply increased, which indicates their role in fibrosis formation; in addition, mast cells degranulate and release a number of inflammatory mediators - leukotrienes, histamine, proinflammatory prostaglandins, etc.

Damage to alveolar epithelial cells

The work of Adamson et al. (1991) established that damage to alveolar epithelial cells promotes the development of underlying connective tissue and interstitial fibrosis. This is due to the fact that along with damage to alveolocytes, regeneration processes occur and regenerating epithelial cells, primarily type 2 alveolocytes, produce fibrosogenic factors: transforming factor, tumor necrosis factor.

The role of lymphocytes in the development and progression of the disease

Lymphocytes participate in pathogenesis as follows:

• an imbalance in the ratio of T-helpers and T-suppressors develops with a distinct decrease in the activity of the latter. As a result, T-helper lymphocytes and B-lymphocytes are activated and, consequently, favorable conditions are created for the production of autoantibodies and the development of autoimmune reactions;
• cytotoxic T-lymphocytes are significantly activated; they are formed from resting T-precursor cells under the influence of interleukin-2 produced by T-helpers and the T-cell differentiation factor. Activated cytotoxic T-lymphocytes directly interact with autoantigens in the interstitial tissue, support the inflammatory process and stimulate the development of fibrosis. Gamma interferon produced by T-lymphocytes also activates macrophages, the role of which in the development of ELISA was discussed above;
• the role of lymphocytes in the development of pulmonary fibrosis increases. Normally, lymphocytes secrete a migrating inhibitory factor, which inhibits collagen synthesis by 30-40%. With ELISA, the production of this factor is significantly reduced or completely stopped. Along with this, lymphocytes produce a large number of lymphokines, which promote the proliferation of fibroblasts and activate the ability of alveolar macrophages to synthesize collagen.

Disturbances in the system "proteolytic activity - antiproteolysis"

High activity of proteolytic enzymes is characteristic of idiopathic fibrosing alveolitis. Neutrophils are the primary sources of proteases - they secrete collagenase, which breaks down collagen, and elastase. Collagenolytic activity is also possessed by cells participating in the fibrosis process - alveolar macrophages, monocytes, fibroblasts, eosinophils. Intensive collagen breakdown, primarily under the influence of neutrophil collagenase, stimulates increased resynthesis of pathological collagen in the pulmonary interstitial tissue. The antiproteolytic system is unable to inactivate high levels of proteases, especially collagenase, especially since the inhibitory effect of a1-antitrypsin is directed primarily at elastase, and to a much lesser extent - at collagenase.

As a result of the imbalance in the protease-antiprotease system, conditions are created for the breakdown of collagen and, to an even greater extent, for the development of fibrosis in the interstitial tissue of the lungs.

Activation of lipid peroxidation

Activation of lipid peroxidation (LPO) is extremely characteristic of idiopathic fibrosing alveolitis. As a result of intensive LPO, free oxygen radicals and peroxides are formed, which have a damaging effect on lung tissue, increase the permeability of lysosomal membranes and promote the release of proteolytic enzymes from them, and stimulate the development of fibrosis. Along with the activation of LPO, the activity of the antioxidant system inhibiting LPO is significantly reduced.

As a result of the action of the above-mentioned pathogenetic factors, damage and inflammation of the epithelial and endothelial cells of the pulmonary parenchyma develops, followed by proliferation of fibroblasts and the development of fibrosis.

Pathomorphology

The modern classification of Katzenstein (1994, 1998) distinguishes 4 morphological forms:

1. Usual interstitial pneumonia is the most common form (90% of all cases of idiopathic fibrosing alveolitis). In the early stages of the pathological process, the morphological picture is characterized by edema, pronounced infiltration of the alveolar walls by lymphocytes, monocytes, plasma cells, eosinophils and the appearance of fibroblast clusters synthesizing collagen. In later stages of the disease, protein detritus, mucin, macrophages, cholesterol crystals are found inside the damaged alveoli, cystically dilated air fields lined with cuboidal alveolar epithelium are formed, type 1 alveolocytes are replaced by type 2 alveolocytes. Normal pulmonary parenchyma is replaced by coarse connective tissue. Macroscopic examination reveals compaction, wrinkling of the lung tissue and a picture of "honeycomb lung".
2. Desquamative interstitial pneumonia - the frequency of this form is 5% among all forms of idiopathic fibrosing alveolitis. The leading pathomorphological sign of this form is the presence of a large number of alveolar macrophages in the alveolar cavity, the alveoli are lined with hyperplastic alveolocytes of type 2. The interalveolar septa are infiltrated with lymphocytes, eosinophils, fibroblasts, but fibrosis is expressed less intensely compared to other forms of idiopathic fibrosing alveolitis. Desquamative interstitial pneumonia is characterized by a good response to treatment with glucocorticoids, the mortality rate does not exceed 25%.
3. Acute interstitial pneumonia - this form was first described by Hamman and Rich in 1935 and it is this form that is usually called by the name of these researchers (Hamman-Rich syndrome). Morphological changes in this form are to some extent similar to the usual interstitial form (pronounced inflammation and edema of the pulmonary interstitium, diffuse damage to the alveoli, proliferation of type 2 alveolocytes, development of interstitial fibrosis). However, the disease is characterized by a severe fulminant course, has a very poor prognosis, and mortality reaches 90%.
4. Non-specific interstitial pneumonia/fibrosis - described by Katzenstein and Fiorell in 1994 and accounts for 5% of all forms of idiopathic fibrosing alveolitis. This form is characterized by the homogeneity of the morphological picture, the intensity of inflammation and fibrosis in the pulmonary interstitium are expressed quite evenly, i.e. they are at the same stage of development, unlike, for example, the most common form of idiopathic fibrosing alveolitis, usual interstitial pneumonia, in which inflammation predominates in the early stages, and intense fibrosis in the later stages. Probably, due to such morphological features, non-specific interstitial pneumonia is characterized by a subacute course, in 80% of patients there is stabilization or even regression of the pathological process, the mortality rate is 11-17%.

Summarizing the morphological picture of idiopathic fibrosing alveolitis, as suggested by M. M. Ilkovich and L. N. Novikova (1998), changes in the lung parenchyma in this disease can be presented in the form of three interrelated stages (phases): interstitial (to a lesser extent alveolar) edema, interstitial inflammation (alveolitis) and interstitial fibrosis, with alveolitis playing a central role. The most pronounced pathomorphological changes are detected in the peripheral (subpleural) parts of the lungs.

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