1, Western medical etiology.
(1) drug-induced: commonly caused by antitumor drugs and bleomycin, methotrexate, cyclophosphamide, etc., antibacterial drugs such as furadantin, penicillins, tetracyclines, para-aminosalicylic acid, as well as acetaminophen iodofurone, phenytoin sodium, penicillamine, etc.
(2) Inhalation of organic dust: mainly caused by inhalation of dust contaminated with actinomycetes and molds. Common diseases such as farmers’ lung, cane dust lung, mushroom lung, mint lung, humidifier lung, air conditioning lung, etc., especially chronic exogenous allergic alveolitis.
(3) Inhalation of harmful gases: such as inhalation of nitric acid, sulfuric acid, hydrochloric acid fumes, toxic and solvent gases, etc., whether acute massive inhalation or chronic small amount of inhalation, can lead to the disease.
(4) Infectious: bacteria, fungi, viruses, mycoplasma, Legionella pneumophila, parasites, etc.
(5) Radioactive damage: such as radiation pneumonia.
(6) Connective tissue diseases: such as rheumatoid arthritis, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, nodular polyarteritis.
(7) Other: such as sarcoidosis, eosinophilic granuloma, multiple neurofibromas, pulmonary-renal hemorrhagic syndrome, etc.
2.Pathogenesis
The pathogenesis of idiopathic pulmonary fibrosis is unclear and may be related to exposure to dust or metals, autoimmunity, chronic and repeated inhalation of trace gastric contents, viral infection and smoking. Genetic predisposition may have a definite influence on the pathogenesis. Pathogenic factors lead to alveolar epithelial damage and destruction of the subepithelial basement membrane, initiating fibroblast recruitment, differentiation and proliferation, resulting in excessive collagen and extracellular matrix production. The damaged alveolar epithelium and inflammatory infiltrated leukocytes secrete TNF-α, TNF-β and IL-8 in an autocrine and paracrine manner.
These inflammatory mediators promote the process of pulmonary fibrosis. An excessive oxidative load in the alveoli may also be involved in the alveolar injury process. The pathogenesis of IPF may be the result of a continuous superposition of inflammation, tissue damage, and repair, with pathogenic factors acting on resident immune cells in the lung to produce an inflammatory or immune response, which may also directly damage epithelial or endothelial cells.
(1) Immune and inflammatory responses The early stages of IPF may produce an anti-specific immune response, with inflammatory responses in the lower airways being the earliest detectable damage to the lung, with increased lymphocytes, macrophages and neutrophils in the interstitium and alveoli, and T lymphocytes playing a dual role in the regulation of lung injury and disease progression in IPF, with T lymphocytes obtained from the alveoli of IPF patients in an activated state, expressing T lymphocytes obtained from the alveoli of IPF patients are activated, express IL-2 receptors and secrete INF-γ. T lymphocytes secrete products that both inhibit fibroblast proliferation and enhance collagen synthesis in fibroblasts, and in addition, T lymphocytes have a tremendous adjuvant effect on B lymphocytes, which is important for enhancing immune complex production.
The generation of specific immune responses within the lung parenchyma is important in influencing the clustering of inflammatory cells in lung tissue. Selective adhesion molecules, adhesion molecule binding elements and immunoglobulins all play an important role in the interaction between inflammatory cells and endothelial cells, and the firm adhesion of many cells depends on intercellular adhesion molecule-1 (ICAM-1) and leukocyte-acting antigen-1 (LFA-1), and TNF- α induces ICAM-1 expression on the surface of endothelial cells, extravascular leukocytes including LFA-1 and platelet endothelial cell adhesion molecules are expressed at the junction of leukocytes and endothelial cells, and urokinase-type fibrinolytic activator (urokinase u- PA) may be a degradation product of protein hydrolases from different tissues during the movement of inflammatory cells from the vasculature to the alveolar lumen.
Direct migration of inflammatory cells in IPF is dependent on a variety of chemicals, chemokines including interleukin -1 (IL-1) monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-Ia (MIP-1a), complement component C5a, cytokines (MCP-1, MIP-1a, fibronectin including RGD acting on macrophages, leukotriene B4 ( LTB4), IL-8 and C5a acting on leukocytes, T lymphocytes, alveolar macrophages, endothelial cells, epithelial cells, and fibroblasts are important sources of these cytokines. urokinase receptor (u-PAR, CD87) is an essential chemokine for monocytes and PMN, and U-PAR may affect leukocyte circulation and activate the adhesion function of complement receptor 3.
(2) Injury Epithelial cell injury is a hallmark of IPF, viral infection and inflammatory cellular products (oxygen radicals, protein hydrolases) are mediators of injury, epithelial cell injury allows plasma proteins to leak into the alveolar lumen, the alveolar basal lamina can also be disrupted during injury, and the presence of activated inflammatory cells (lymphocytes, macrophages, PMN) perpetuates the development of alveolar wall injury.
(3) Repair of fibrosis Successful repair of injured alveoli requires removal of plasma proteins entering the alveolar lumen, replacement of the damaged alveolar wall, and restocking of the damaged extracellular matrix. The alveolar exudate formed during the inflammatory response includes many cytokines and mediators such as growth factors (platelet growth factor, transfer growth factor-beta, insulin-like growth factor-I), fibronectin, thromboxane, and fibrinopeptides.
However, fibrin degradation in the BAL of IPF patients is inhibited by increased levels of fibrinogen activator and fibrinolytic enzymes such as fibrinogen activation inhibitor-1 (PAI-1), and similarly, fibronectin in the alveolar lumen is also inhibited. Similarly, fibronectin in the alveolar lumen is also inhibited, and if the alveolar exudate is not cleared, fibroblasts invade, proliferate, and produce new matrix proteins, turning the fibrin-rich exudate into a scar.
Arachidonic acid metabolism also plays an important role in the fibrotic response to IPF, and interleukins have a direct effect on fibroblasts and other mesenchymal cells, stimulating fibroblasts to release chemokines that promote cell proliferation and collagen synthesis. An important feature of alveolar repair is epithelial reformation of the alveolar basement membrane, and to complete this process, type II alveolar epithelial cells proliferate, and eventually the basement membrane surface is repaired and Local exudate mechanization, a process that undoubtedly occurs under the influence of keratinocyte growth factor and hepatocyte growth factor, which regulate the proliferation and migration of epithelial cells. During the formation of IPF, epithelial cells are lost and alveoli collapse, resulting in a mass of scarring when a large number of alveoli are involved.
3.Pathological changes
The pathological changes of idiopathic pulmonary fibrosis are related to the severity of the lesion. The main feature is the heterogeneous distribution of lesions within the lung, with normal, interstitial inflammation, fibroplasia, and cellular lung changes seen in the same low magnification field, with marked lesions in the lower lung and subpleural areas. The alveolar wall is thickened with collagen deposition, increased extracellular matrix, and focal mononuclear cell infiltration. Inflammatory cells are infrequent and usually confined to areas of collagen deposition or cellular lung. Small aggregates of type II alveolar epithelial cells may be seen in the alveolar lumen. Foci of cellular lung air sacs, fibrosis, and fibrous proliferation may be seen.
The main pathologic features of IPF include varying degrees of fibrosis and inflammation of the alveolar septa (interstitium) and alveoli, and because many inflammatory lung diseases can have similar manifestations, granulomas, vasculitis, inorganic pneumoconiosis, or organic pneumoconiosis must be excluded. In the early stages of the disease, the alveolar structure may remain intact, but the alveolar wall is edematous and thickened, and the interstitial inflammatory cells accumulate, mainly mononuclear cells (e.g., lymphocytes, plasma cells, monocytes, macrophages), but also scattered multinucleated neutrophils and eosinophils.
In the early stages of the disease, focal aggregates of alveolar macrophages are seen, and macrophages are absent in the alveoli of moderate or progressive IPF. In advanced stages of the disease, there is a large amount of interstitial lung collagen, intracellular matrix, fibroblasts, and inflammatory cells, which are rare or even absent, and in patients with longer disease duration, alveolar epithelial hyperplasia and squamous metaplasia can be seen. The presence or absence of fibrous tissue around the cystic cavity can distinguish emphysema from cellular lung.
4. Chinese medical etiology of interstitial lung fibrosis
The main aspects of the pathogenesis are lung dryness and yin injury and lung qi deficiency and coldness, which are mostly seen clinically in patients with yin deficiency and dryness and heat, or aggravated by acute infection. Deficient cold lung impotence is mostly due to internal injuries such as prolonged coughing, prolonged asthma, etc. that consume qi and injure yang, or deficient heat lung impotence that is prolonged for a long time, with yin injury and yang, and deficient lung with cold and loss of moistening. Clinically, this is most often seen when there is a deficiency of yang in the body, or chronic illnesses that last for a long time, such as chronic bronchitis and bronchial dilatation. It is generally believed that deficiency-heat lung impotence caused by lung dryness and fluid injury is the most common clinical condition. In milder cases, the manifestation of deficiency of lung yin is more common, while in more severe cases, the manifestation of deficiency of qi and yang is more common; in the early stage, deficiency of lung yin is more common, while in the late stage, deficiency of qi and yang is more common.
Lung impotence is mostly caused by dry-heat evil that consumes lung yin. Dry-heat evil can also burn the blood channels, and blood overflowing outside the veins becomes stasis of blood; or heat evil can burn the fluids, stagnate the blood, and make stasis of blood; deficiency of qi-yin can also lead to stasis of blood, and qi deficiency is unable to transport blood, and blood flow stagnation becomes stasis of blood. Once stagnant blood is formed, it can in turn affect the smooth flow of qi, making it difficult for yin, fluid and yang to reach the lungs, and the loss of lung moistening further aggravates pulmonary impotence.
In clinical practice, patients with pulmonary interstitial fibrosis have symptoms, signs and laboratory tests that show stasis of blood, such as dullness of the face, cyanosis of the lips and increased blood viscosity, etc. In advanced stages, when the right heart function is affected, leading to right heart insufficiency, stasis of blood in the body circulation can be seen.