Idiopathic fibrosing alveolitis: causes and pathogenesis

Causes of idiopathic fibrosing alveolitis

The causes of idiopathic fibrosing alveolitis have not been fully established. The following possible etiological factors are currently being discussed:

• virus infection - the so-called latent, "slow" viruses, primarily the hepatitis C virus and the human immunodeficiency virus. The possible role of adenoviruses, the Epstein-Barr virus (Egan, 1995) is also assumed. There is a point of view about the dual role of viruses in the development of idiopathic fibrosing alveolitis - viruses are the primary triggers of the development of damage to lung tissue and, in addition, the virus replicates in the already damaged tissue, which naturally contributes to the progression of the disease. It is also established that the viruses interact with the genes that regulate cell growth, and thus stimulate collagen production, fibro-oocyte formation. Viruses can also increase the already existing chronic inflammation;
• ecological and professional factors - there are data on the relationship of idiopathic fibrosing alveolitis with prolonged professional contact with metal and wood dust, brass, lead, steel, some types of inorganic dust - asbestos, silicate. The etiological role of aggressive etiological factors is not ruled out. However, it should be emphasized that these occupational factors cause pneumoconiosis, and, with reference to idiopathic fibrosing alveolitis, can probably be considered as triggering factors;
• genetic predisposition - the role of this factor is confirmed by the presence of family forms of the disease. It is assumed that the genetic predisposition to idiopathic fibrosing alveolitis is based on hereditary polymorphism of genes encoding proteins involved in processing and presentation of antigens to T lymphocytes. In recent years in the development of idiopathic fibrosing alveolitis, a genetic defect-deficit of a1-antitrypsin (this contributes to the destruction of interalveolar septa, interstitial tissue, development of pulmonary emphysema) and a decrease in T-suppressor function of T-lymphocytes plays a large role (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 lung tissue and the subsequent development of an intense and widespread fibrotic process.

Pulmonary interstitial tissue is a connective tissue matrix of the alveolar wall, consisting primarily of type I collagen and surrounded by epithelial and endothelial basal membranes. Alveolar walls are common for two adjacent alveoli, the alveolar epithelium covers the wall from two sides. Between the two sheets of the epithelial lining is interstitium, in which the bundles of collagen, reticular and elastic fibers are located, as well as cells - histiocytes, lymphocytes, neutrophilic leukocytes, fibroblasts and a network of blood capillaries. Alveolar epithelium and endothelium of capillaries lie on the basal membrane.

At present, the following major pathogenetic factors of idiopathic fibrosing alveolitis are known.

Development of persistent autoimmune processes in pulmonary interstitium

Under the influence of an unknown etiological factor on the cell membranes of the alveoli and interstitial lung tissue, antigen expression occurs. The following can serve as autoantigens:

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

To autoantigens, antibodies are produced. In 80% of patients with idiopathic fibrosing alveolitis, autoantibodies to the protein of lung tissue and collagens I, P, III and IV types are detected in the blood. Further, immune complexes are formed in the lungs (autoantigens + autoantibodies), the immune-inflammatory process develops in the pulmonary interstitium, acquiring persistent flow.

Proliferation and activation of alveolar macrophages

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

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

Activation and proliferation of neutrophilic leukocytes, eosinophils, mast cells

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

• activation of neutrophilic leukocytes - neutrophils accumulate in 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 - is accompanied by the release of a number of substances that exert a pro-inflammatory and damaging effect (leukotrienes, proteases, oxygen radicals, eosinophilic cationic protein, large base protein, etc.);
• accumulation and activation of mast cells - in the areas of fibrosis, the number of mast cells is dramatically increased, which indicates their role in fibrosing; In addition, mast cells degranuliruyut and secrete a number of mediators of inflammation - leukotrienes, histamine, pro-inflammatory prostaglandins, etc.

Damage to epithelial alveolar cells

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

The involvement 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 with a distinct decrease in activity of the latter develops. As a result, T-lymphocytes-helpers 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 -cell precursors by the action of interleukin-2, produced by T-helper cells, and the differentiating factor of T-cells. 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 is mentioned above;
• the role of lymphocytes in the development of pulmonary fibrosis increases. Normally, lymphocytes release a migrating inhibitory factor that inhibits the synthesis of collagen by 30-40%. With ELISA, the production of this factor is significantly reduced or completely discontinued. Along with this, lymphocytes produce a large number of lymphokines that promote the proliferation of fibroblasts and activate the ability of alveolar macrophages to synthesize collagen.

Violations in the system "proteolytic activity - antiproteolysis"

For the idiopathic fibrosing alveolitis, a high activity of proteolytic enzymes is characteristic. The sources of proteases are primarily neutrophils - they release collagen, splitting collagen, and elastase. Collagenolytic activity is also possessed by cells participating in the process of fibrosis - alveolar macrophages, monocytes, fibroblasts, eosinophils. Intensive collagen degradation, primarily under the influence of neutrophil collagenase, stimulates the enhanced resynthesis of pathological collagen in the pulmonary interstitial tissue. The anti-proteolytic system is not able to inactivate high levels of proteases, especially collagenase, especially since the inhibitory effect of a1-antitrypsin is directed primarily to elastase, and to a much lesser extent to collagenase.

As a result of an imbalance in the protease-antiprotease system, conditions are created for the cleavage of collagen and, even more, for the development of fibrosis in the interstitial lung tissue.

Activation of lipid peroxidation

Activation of lipid peroxidation (LPO) is extremely characteristic of idiopathic fibrosing alveolitis. As a result of intense LPO free oxygen radicals are formed, peroxides that have a damaging effect on lung tissue, increase the permeability of lysosomal membranes and promote the release of proteolytic enzymes from them, 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 abovementioned pathogenetic factors, damage and inflammation of the epithelial and endothelial cells of the pulmonary parenchyma develop, followed by proliferation of fibroblasts and the development of fibrosis.

Pathomorphology

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

1. Ordinary 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, expressed by the infiltration of alveolar walls by lymphocytes, monocytes, plasma cells, eosinophils and the appearance of clusters of fibroblasts synthesizing collagen. In later stages of the disease, protein detritus, mucin, macrophages, cholesterol crystals are detected inside the damaged alveoli, cystically widened airway fields lined with cuboidal alveolar epithelium are formed, and type 1 alveolocytes are replaced by type 1 alveolocytes. The normal pulmonary parenchyma is replaced by a coarse connective tissue. Macroscopic examination reveals compaction, wrinkling of the lung tissue and a picture of the "cellular lung".
2. Desquamative interstitial pneumonia - the frequency of this form is 5% among all forms of idiopathic fibrosing alveolitis. The leading pathomorphological feature of this form is the presence in the cavity of the alveoli of a large number of alveolar macrophages, the alveoli are lined with hyperplastic alveolocytes of type 2. The interalveolar septa are infiltrated by lymphocytes, eosinophils, fibroblasts, but fibrosis is less pronounced compared to other forms of idiopathic fibrosing alveolitis. Desquamative interstitial pneumonia is characterized by a good response to treatment with glucocorticoids, lethality 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 commonly called by the name of these researchers (the Hamman-Rich syndrome). Morphological changes in this form are to some extent similar to the usual interstitial form (pronounced inflammation and pulmonary interstitial edema, 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, lethality reaches 90%.
4. Nonspecific interstitial pneumonia / fibrosis is 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 pattern, the intensity of inflammation and fibrosis in pulmonary interstitium is fairly uniform, i.e. Are at one stage of development, in contrast to, for example, the most frequent form of idiopathic fibrosing alveolitis of ordinary interstitial pneumonia, in which inflammation predominates in the early stages, and intensive fibrosis prevails in the late stages. Probably, in connection with such morphological features, nonspecific interstitial pneumonia is characterized by subacute flow, in 80% of patients stabilization or even regression of the pathological process is observed, lethality is 11-17%.

Summarizing the morphological picture of idiopathic fibrosing alveolitis, it is possible to present changes in the lung parenchyma in this disease in the form of three interrelated stages (phases): interstitial (less alveolar) edema, as suggested by MM Ilkovich and LN Novikova (1998) , interstitial inflammation (alveolitis) and interstitial fibrosis, with the central place belongs to the alveolitis. The most pronounced pathomorphological changes are revealed in the peripheral (subpleural) sections of the lungs.

[1], [2], [3], [4], [5], [6], [7], [8]