The formation of lung inflammation in patients with COPD is mainly associated with congenital and adaptive immunity, among them, the congenital immune contains neutrophils and macrophages, eosinophils and mast cells, natural killer cells, γδ T cells, such as inflammation, fine dominant immune response, adaptive immunity refers to T and B lymphocytes or dominant immune response. In this group of patients, the number of macrophages, neutrophils, and lymphocytes is increased, and these cells are mainly located in the pulmonary blood vessels, peripheral airway, and parenchyma of the lung. However, some patients may also show an increase in the number of eosinophils, ILC2, or Th2 cells. At the same time, airway and alveolar epithelial cells and endothelial cells and other structural cells are also activated. Inflammatory cells can release different inflammatory mediators together with other cells (such as epithelial cells and other structural cells) (4). Studies have confirmed that the lack of local IgA can indirectly lead to bacterial translocation and small airway inflammation, which develops into airway remodeling and eventually irreversible airflow restriction (13).

Macrophages play an important role in the chronic inflammation of COPD patients ( Figure 2 ). The number of macrophages in the bronchoalveolar lavage fluid (BALF) and sputum of COPD patients can be significantly increased, typically reaching 5-10 times higher than normal values. Macrophages often accumulate at sites of alveolar wall destruction, a phenomenon we can observe in patients with emphysema and COPD, where the number of macrophages correlates with the severity of emphysema. Studies of this phenomenon have shown that macrophages are activated by factors such as cigarette smoke extracts and release inflammatory mediators such as TNF-α, CXCL1, CXCL8, CCL2, leukotriene (LT) B4 and reactive oxygen species (ROS), etc., which mediate the inflammatory response (14). Large increases in macrophages are seen in COPD patients and smokers and are mainly associated with increased circulating chemokines CCL2 and CXCL1, both of which are also found to be significantly elevated in the sputum and BALF of COPD patients (15).

Macrophages have different phenotypes with different activation pathways that lead to different organismal responses. Previous studies have shown that mouse M1-type macrophages are pro-inflammatory, whereas M2-type macrophages are anti-inflammatory, release IL-10, and exhibit significant phagocytic activity (16). However, these differences were not evident in human macrophages, probably because the macrophages in COPD patients are mainly M1-type, but further studies are needed to prove this (17).

Macrophages can secrete elastolytic enzymes, including MMP-2, MMP-9, and MMP-12 (18). MMP-9 is produced by alveolar macrophages and is one of the molecules that mediates the inflammatory response in COPD patients. Compared to smokers, alveolar macrophages in COPD patients secrete more inflammatory proteins and have higher elastolytic activity, suggesting increased activation of macrophages in COPD patients (19). Much of the upregulation of inflammatory proteins is regulated by the transcription factor NF-κB in macrophages, which is extensively activated when the disease is exacerbated, resulting in massive production of inflammatory proteins (20). This inflammatory protein can also be further secreted upon exposure to cigarette smoke, thereby accelerating the rate of inflammation. Macrophages mediate this mechanism even when kept continuously in culture for more than 3 days, so that macrophages in smokers and nonsmokers are fundamentally different (4).

Monocytes from COPD patients exhibit a stronger chemotactic response to CXCL1 than monocytes from smokers and non-smokers (21). In addition, macrophages can also exert chemotactic effects on CD8+ Tc1 and CD4+ Th1 cells by binding to CXCR3, a chemokine receptor expressed by CD8+ Tc1 and CD4+ Th1 cells, to release CXCL9, CXCL10 and CXCL11 chemokines (22).

It has been shown that in healthy individuals and smokers, corticosteroids inhibit the release of CXCL8, TNF-α and MMP-9 from macrophages, thereby alleviating the inflammatory response, but in patients with COPD, where the inflammatory response is mainly mediated by cytokines, chemokines and proteases, corticosteroid use is ineffective (23) and fails to work in macrophages of COPD patients, showing a relatively ineffective (19). Resistance to corticosteroids in COPD patients may be due to decreased histone deacetylase (HDAC) 2 activity due to increased secretion of cytokines (e.g., TNF-α and CXCL8) in macrophages (24).

Both alveolar-derived macrophages and monocyte-derived macrophages in patients with COPD exhibit reduced phagocytic uptake of bacteria, which may be the result of long-term colonization of the lower airways by bacteria such as Haemophilus influenzae or Streptococcus pneumoniae (25), which is present in at least 50% of patients with COPD and may increase the risk of acute exacerbation of COPD, in addition to causing chronic inflammation (26). In addition, macrophage phagocytosis, such as phagocytosis of apoptotic cells, is also defective in COPD patients, which may contribute to the persistence of inflammation in COPD patients (27). The cause of the defective phagocytosis of macrophages is still unclear, and some findings suggest that it may be related to the defective function of cellular microtubules, which are closely related to cytophagy (28).

Increased sputum and BALF neutrophilia is a typical feature of COPD, and this neutrophil-induced inflammation can caused by regular exposure to cigarette smoke, infectious agent and oxidative stress (5). Neutrophil recruitment to the airways and parenchyma involves initial adhesion to endothelial cells through E-selectin, which is upregulated on endothelial cells in the airways of patients with COPD. Adherent neutrophils migrate into the respiratory tract under the direction of various neutrophil chemotactic factors, including LTB4, CXCL1, CXCL5, and CXCL8, levels of which are increased in airways of patients with COPD (4).

Neutrophils secrete several serine proteases including neutrophil elastase (NE), cathepsin G, proteinase-3, MMPs and myeloperoxidase (MPO) which may contribute to the alveolar damage (4, 29). Alpha‐1 antitrypsin (AAT) is a serum inhibitor of serine proteinases. AAT deficiency (AATD), which is due to a genetic abnormality in the antiproteases, is associated with neutrophilic inflammation in the lung and accounts for less than 1% of COPD patients (5). AATD that results in early onset emphysema, usually in smokers, due to inactivate NE and other serine proteases (30). Despite these theoretical mechanisms, however, only a few patients have AATD, and, thus, it has been difficult to explain why the lung is not normally protected in the majority of COPD patients.

It has been suggested that the size and extent of the neutrophil traffic may be related to the pathological changes that occur in individuals with COPD in case of emphysema (31). The NE is stored within neutrophil azurophil granules which diffuse away from the granule until the concentration has fallen sufficiently for the enzyme to be completely inactivated by the local concentration of AAT. AAT limits rather than prevents neutrophil protease-related damage. It binds to proteases via a one-to-one molar ratio. However, at the location where a degranulating neutrophil is located, the concentration of NE is much higher than that of AAT. This results in obligatory tissue damage around each degranulating cell until the concentration of protease is reduced by diffusion into the local tissue environment. Thus, the role of AAT is to slow down rather than completely stop the damage caused by these proteases (32). This theoretical relationship may explain not only the tissue destruction that occurs in the absence of AATD, but also the extensive destruction seen in deficient subjects. It can be predicted that in people who do not have AATD, there will always be some tissue damage in the immediate vicinity of a degranulating neutrophil. When the AAT concentrations are significantly reduced (as in patients with AATD), the area of damage that will occur can be predicted to be far greater. This would explain not only the increased susceptibility of patients with AATD to tissue damage, but it also provides an explanation for the development of similar but limited damage in non-AATD subjects.

The above findings have implications for the precise treatment of COPD. The World Health Organization (WHO) recommends that especially in areas with a high prevalence of AATD, all patients with COPD should be screened for AATD (1). AAT augmentation therapy with infusion of human plasma derived purified AAT has been shown to slow progression (33) ( Figure 3 ).

As a heterogeneous lung lesion, COPD has multiple subtypes. With the deeper understanding of the inflammatory mechanisms of COPD, it has been found that neutrophilic inflammation is the most common type of inflammation, but 20% to 40% of patients also belong to the type 2 inflammatory endotype, characterized by elevated eosinophils (EOS) (34, 35). It is generally accepted that type 2 inflammation is characterized by upregulation of the expression of type 2 cytokines, such as IL-4, IL-5, and IL-13, produced by Th2 and ILC2 (36). Currently, the mechanism of airway type 2 inflammation formation in COPD is unclear. Some studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) and CCL5 secreted by the airway epithelium in patients with COPD may promote the survival and recruitment of EOS in the airways (37). Acute exacerbations are more frequent in patients with COPD characterized by type 2 inflammation compared with the predominantly neutrophil-driven, non-type 2 inflammatory endotype (35).

The differences in eosinophil counts may determine different responses to inhaled corticosteroid (ICS) therapy (38). By modeling eosinophil count as a continuous variable, a post hoc analysis showed that ICS-containing regimens had little to no effect when blood eosinophil count was less than 100 cells/μL, and thus this threshold could be used to identify patients with a low likelihood of benefit from treatment with ICS (39). In addition, decreased eosinophils in blood and sputum were associated with an increase in proteobacteria, primarily Haemophilus, as well as an increase in bacterial infections and pneumonia (40, 41). ICS are anti-inflammatory drugs used in combination with one or two long-acting bronchodilators (LABDs) for the treatment of COPD. Studies have shown that ICS reduce exacerbation rates, improve quality of life, and prevent mortality in COPD patients with a history of exacerbations (42, 43). Accordingly, GOLD recommends the use of eosinophil testing for COPD patients with a history of exacerbations in clinical practice, despite their appropriate use of LABDs, to identify patients who are best suited to receive ICS therapy (1). The threshold of a blood eosinophil count ≥ 300 cells/μL identifies the top of the continuous relationship between eosinophils and ICS, and can be used to identify patients with the greatest likelihood of treatment benefit with ICS. The thresholds of < 100 cells/μL and ≥ 300 cells/μL should be regarded as estimates, rather than precise cut-off values, that can predict different probabilities of treatment benefit (38, 44). There is no clear evidence that ICS treatment reduces blood eosinophil count, so it retains their predictive value independent of ICS treatment.

The pathogenesis of patients with COPD is complex, and although it is currently recommended that group E patients with blood eosinophil count ≥300/μL should be treated with the triple therapy of “ICS + LAMA + LABA”, some patients are still poorly controlled after the triple therapy [1]. The New England Journal recently published a new clinical study revealing the efficacy of using dupilumab in the treatment of patients with COPD with type 2 inflammatory features. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation. The results showed that in COPD patients with type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo (45) ( Figure 4 ). In summary, biologically targeted therapy for type 2 inflammation may be a new treatment option.

Dendritic Cells (DCs) also play an important role in the pathogenesis of COPD. DCs are an important component of the immune system, mainly involved in initiating the immune response and regulating the innate immune response (68). In patients with COPD, the number of DCs in the airways is altered, and smoking causes DCs to release inflammatory chemokines, such as CCL20, which play an important role in the pathogenesis of COPD (69). Studies have shown that dendritic cell accumulation exists in the bronchial mucosa of patients who smoke and COPD, and that cigarette smoke alters dendritic cell maturation and function, thereby affecting the immune response in the lungs (70). Specifically, cigarette smoke activates epithelial cells and macrophages, causing them to release a variety of chemokines that attract and activate inflammatory cells in the lungs, including DCs (69, 71). These inflammatory cells, along with macrophages, polymorphonuclear leukocytes (PMN), and epithelial cells, release proteases such as MMP and NE, leading to elastin degradation and emphysema formation (69, 72). In addition, DCs, by releasing pro-inflammatory chemokines, may be involved in maintaining neutrophilic airway inflammation, which in turn leads to emphysematous lung tissue destruction (69). DCs are not only involved in the triggering of COPD pathogenesis, but may also play an important role in the pathologic process of COPD by modulating effector CD8+ T cell responses (69). Interventions targeting the function of DCs may provide new avenues for the treatment of COPD.