Airway remodeling in asthma and chronic obstructive pulmonary disease

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Xiao Feng XinBronchial asthma (asthma) and chronic obstructive pulmonary disease (COPD) were airway inflammatory disease, although its patho


Xiao Feng Xin

Bronchial asthma (asthma) and chronic obstructive pulmonary disease (COPD) were airway inflammatory disease, although its pathogenesis is different, but the airway inflammation can lead to airway wall thickening and pulmonary parenchymal changes in the structure, thus contributing to airway stenosis and limited flow. Such a process characterized by airway wall thickening and inflammation has been reported in asthma and COPD, but the infiltration and remodeling of airway inflammatory cells are different in these two diseases [1]. This paper mainly expounds the main differences between asthma and airway remodeling in COPD, in order to better understand the mechanism of airway remodeling, to seek a new target for the treatment of these diseases.

1 airway inflammation and its relationship with remodeling

The pathological changes of asthma and airway inflammation of COPD not only in the central airway, also exist in the peripheral airways, the pathological changes including the expression and composition of airway inflammatory cell infiltration and cytokine remodeling etc..

1.1 infiltration of inflammatory cells

The activity of eosinophils was strongly associated with the severity of asthma and airway hyperresponsiveness in asthmatic airways. Although there was infiltration of eosinophils in the airway, the distribution of eosinophils in the small airways and large airway wall was different. In the small airway eosinophilic airway wall mainly distributed in the peripheral (in smooth muscle and alveolar adhesion between, in the large airway), eosinophils are mainly distributed in the airway wall within the week (in smooth muscle cells and basement membrane between). In severe asthma, there is a clear neutrophil inflammation. The number of neutrophils in the airway was significantly increased in patients with acute exacerbation of asthma, severe steroid dependent asthma, or death from asthma (2).

The airway inflammation of COPD is characterized by infiltration of T lymphocytes, macrophages and neutrophils. Airway mainly by neutrophils and macrophages, in COPD patients with sputum and bronchoalveolar lavage fluid (BALF) in the number of these cells increased also illustrates this point. In the airway wall of COPD patients, the infiltration of T lymphocytes was mainly CD8+T lymphocytes, while in asthma patients were mainly CD4+T lymphocytes. Importantly, the increase in the number of CD8+T lymphocytes was associated with the airflow limitation in patients with COPD, which further confirmed the role of CD8+T lymphocytes in the development of airway inflammation in COPD. The role of CD8+T lymphocytes is unknown, but they can lead to tissue destruction granzyme and perforin 3.

The assessment of smoking history of patients with COPD airway inflammation, macrophage and eosinophil number is increased, while CD4+ and CD8+T lymphocytes was significantly increased, suggesting that CD4+ and CD8+T lymphocytes may not play a major role in inflammation and smoking history airway in COPD patients with chronic persistent, CD8+T lymphocytes mainly involved in acute airway COPD patients with inflammation caused by smoking, 4. In patients with mild to moderate COPD smoking, there was no significant infiltration of neutrophils in the airway wall. However, when COPD was severe, neutrophil infiltration was evident, suggesting that neutrophil infiltration was associated with the severity of the disease, as was the case with asthma (5).

1.2 cytokine expression

The aggregation and activation of inflammatory cells in airway are regulated by various cytokines. The expression of cytokines in asthma and COPD patients was different. In asthma, T helper 2 (Th2) T lymphocytes and eosinophils play a major role in airway inflammation, and many cytokines regulating its function are overexpressed in the airways of asthmatic patients. These cytokines can be divided into the following categories: Th2 like cytokines such as interleukin (IL) -4, IL-5, IL-9 and IL-13; proinflammatory cytokines such as tumor necrosis factor (TNF) alpha and IL-1 beta; chemokines such as RANTES (regulation of cell activity, normal T cells expressed and secreted) and eotaxin, monocyte chemoattractant protein (MCP) -1; growth factors including transforming growth factor beta (TGF) and epidermal growth factor (EGP). On the other hand, the expression of cytokines, such as IL-10 and IL-12, which decrease the activity of inflammatory cells is reduced.

For COPD, proinflammatory cytokines and chemokines play a major role. Some data indicate that induced sputum, bronchoalveolar lavage and bronchial biopsies of IL-6, IL-1 beta, TNF- alpha, IL-8 and MCP-1 levels were elevated in patients with COPD. Eosinophils and neutrophils were significantly increased in the acute exacerbation of COPD, and the expression of chemokines such as eosinophil chemotactic factor was also increased (6).

1.3 the relationship between inflammation and remodeling

Acute inflammation is a response to tissue injury, which can protect the host and restore the damaged tissue to maintain its normal function. However, if the acute inflammation is persistent and repeated, it can be changed into chronic inflammation and airway remodeling and the change of lung parenchyma. COPD patients with the development of their forced expiratory flow rate decreased significantly (also can be seen in some patients with asthma) that this point. There is no convincing evidence that airway remodeling is entirely dependent on the formation of chronic inflammation. The process of chronic inflammation seems to be different from that of airway remodeling.

It is obvious that cytokines play an important role in airway inflammation and remodeling of airway wall. In the lung, IL-5, IL-9 and IL-4 IL-13 can cause hyperplasia of goblet cells and mucous membrane of subepithelial fibrosis and airflow limitation, with or without airway hyperresponsiveness, these characteristic changes of asthma. After over expression of interleukin 11 with the proliferation of airway smooth muscle (ASM). Contrary to these cytokines, IL 13 and interferon (INF) - gamma overexpression can lead to the destruction of alveolar wall, the expansion of the cavity and so on. Increased expression of growth factor also plays an important role in airway remodeling. The increased expression of TGF- and endothelin, together with the activation of fibroblasts and the over expression of tissue inhibitor of metalloproteinases, seem to be involved in the formation of airway wall fibrosis. Platelet growth factor and EGF are potent stimulators of known ASM proliferation. By increasing the expression of mucin genes, EGF may also be associated with increased mucus secretion (7).

2 airway structure changes

Airflow limitation in COPD and asthma patients is due to the presence of chronic inflammation, which leads to airway remodeling and changes in lung parenchyma. The mechanism of airway remodeling has not been fully elucidated, but it is closely related to chronic inflammation.

2.1 epithelial damage

The airway epithelium is damaged and shed, and the degree of asthma is different. The process of epithelial injury induced repair can lead to the complete repair of columnar epithelium, as well as the proliferation of squamous metaplasia and / or goblet cells. From the histological point of view, the destruction and shedding of airway epithelium are characteristic pathological changes of asthma. The observed loss of epithelial cells in the sputum of asthma bundles (called Creola), increased loss of epithelial cells in BALF and biopsy specimens in airway epithelium, and in related injury observed in the epithelium of platelet and raw fiber material (possibly fibrin) aggregation, related to the degree of these changes with the airway hyperresponsiveness. In contrast, the loss of epithelium was rarely observed in bronchial biopsy specimens from COPD patients. Metaplasia of squamous and goblet cells is a unique feature of COPD.

Interestingly, the mitotic activity of the airway epithelium, which is necessary for tissue repair, may be suppressed in asthma, but not in COPD, which may explain the abnormal repair after epithelial injury. Some studies showed that repair incomplete injury or chronic inflammation leads to airway epithelial cells of epithelial origin before various factors and growth factors, such as IL - 8, eosinophil activation factor, more sustained activation of RANTES, EGF and granulocyte macrophage colony stimulating factor and long-term secretion. The sustained release of these cytokines and growth factors may contribute to the changes of airway structure in asthmatic patients, including the thickening of the reticular basement membrane (RBM), the hypertrophy of ASM and mucus glands, etc. (8).

2.2 thickening of the reticular basement membrane (RBM)

Thickening of RBM is the main characteristic of asthma, but not in COPD (2,9). The thickening of RBM in asthmatic patients is due to the increase of collagen I, III and IV in RBM. However, recent data suggest that RBM may also be due to thickening of proteoglycan matrix with reticulin fiber, fibronectin and tenasin rich through the absorption of water causes permeability edema caused by 9. The thickening of RBM occurs in the early stages of asthma, and most studies show that there is no link between the thickening of the course and severity of asthma and recurrent inflammation (10).

There was no RBM thickening in the patients with COPD, but the fibrosis of the airway wall was characteristic change (5). Fibrosis of the peripheral airway is an important factor in the airway stenosis in patients with COPD, and can induce airflow limitation. In addition, the changes of inflammation, such as airway edema, increased mucus secretion, the destruction of alveolar wall, and the loss of elastic recoil, are important factors of COPD airway stenosis. COPD airway fibroblasts, myofibroblasts and extracellular matrix accumulation of connective tissue by numerous cells (such as macrophages and epithelial cells) mediated by these cells to produce TGF, PDGF, ß insulin-like growth factor binding protein 1 and fiber 11.

2.3 bronchial smooth muscle hypertrophy

Remodeling of airway wall in asthma is characterized by increased structural changes, including the destruction of RBM epithelial thickening, ASM and mucous gland hypertrophy, all these changes can lead to reduced thickening of the airway wall and obvious airway caliber. The characteristics of COPD airway wall remodeling include squamous and goblet cell metaplasia, hypertrophy of mucous glands, and subepithelial fibrosis. These structural changes contribute to the formation of airflow limitation by increasing airway resistance. The presence of mucus and inflammatory exudate makes the airflow limitation more apparent, which not only blocks the airway, but also increases the surface tension, which is likely to cause airway closure [2, 9].

The increase in ASM due to hypertrophy and / or hyperplasia may explain the narrowing of the airway lumen and the narrowing of the airway diameter in patients with severe asthma. One of the reasons for the increase of ASM in asthma is the involvement of muscle fiber, which is different from that of myofibroblasts in terms of ultrastructural features. These cells are thought to represent the disappearance of specific cell morphology after the muscle cells, which move up the subcutaneous region to form a new ASM beam. In COPD, an increase in ASM occurred in small airways rather than in large airways, whereas in asthma, an increase in ASM occurred earlier in large airways (9).

2.4 goblet cell hyperplasia and hypertrophy of submucosal glands

The excessive production of mucus is a clinical symptom in patients with asthma and COPD, which is consistent with the histopathological findings of goblet cell hyperplasia, submucosal gland hypertrophy, and airway characteristics of asthma and COPD. Interestingly, although the submucosal glands in the asthma maintained a normal proportion of serous and mucous acini, there was a disproportionate increase in mucus acini and loss of serous fluid in COPD (9). Because the serous exudates contain a series of antibacterial substances, including the secretion of lactoferrin and composition of lysosomes and secretory IgA, they decrease in COPD may cause respiratory tract infection.

3 changes in the vascular system

The dilation, congestion and edema of the bronchial mucosa are the main characteristics of the fatal asthma and the cause of the swelling and hardening of the tracheal wall. These changes of tracheal wall vessels, may be partly due to vascular proliferation in bronchial wall (angiogenesis) caused by the latter exists in mild asthma, especially in severe hormone dependence is more obvious 12 type of asthma. These changes are caused by chronic allergic inflammation, or because of chronic (or potentially) viral, mycoplasma, or bacterial infections. Airway vascular proliferation may be involved in airway remodeling of asthma from the following aspects: (1) vascular volume increased, the thickness of airway wall increased; (2) promote airway smooth muscle cells and fibroblasts hyperplasia / hypertrophy and secretory function of vascular regeneration; (3) the expression of vascular adhesion molecules resulted in increased infiltration of inflammatory cells; (4) the proliferation of vascular regeneration and airway epithelial metaplasia may also be about 13. The change of COPD vascular system is mainly manifested in the structure. In patients with moderate to severe COPD, the pulmonary vascular pressure increased during the activity, and the pulmonary artery structure changed, which was consistent with the occurrence of pulmonary hypertension. Compared with non smokers who do not have airway obstruction, there is a small airway obstruction and small blood vessels in smokers


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