AAT, as other secreted proteins, requires processing by the endoplasmic reticulum (ER) and Golgi apparatus. The stable conformation of AAT is established through protein folding (18). AAT synthesis is regulated by both ER cargo receptors and biosynthetic quality control systems. The process of AAT monomer extension to polymer secretion is not accomplished in cells with disruption of the ER cargo receptors lectin mannose binding 1 and surfeit protein locus 4. ER cargo receptors modulate the synthesis of AAT within the ER and can influence the accumulation of polymeric AAT by controlling the concentration of precursor monomers and facilitating the secretion of polymers (19). The biosynthetic quality control system first enhances the structural maturation of AAT and subsequently selectively eliminates immature molecules, thereby promoting AAT secretion (20). The transport pathway of AAT is intricate; it is transported to the pulmonary epithelium and interstitium through apical endothelial cells via endocytosis and transcytosis, with secretion occurring at the basolateral surface (21). Additionally, AAT undergoes bidirectional uptake and secretion between lung endothelial cells and alveolar epithelial cells, as well as the air chambers (22). The conformational polymorphisms of the AAT protein contribute to the complexity of its biological functions.

AAT is a multifunctional protein with several key roles, including anti-inflammatory, antibacterial and antiapoptotic functions, as well as the inhibition of serine proteases (23). As a unique endogenous anti-inflammatory agent, AAT inhibits the synthesis and release of inflammatory mediators while suppressing the production of inflammatory cytokines. Its anti-inflammatory activities include NF-κB-dependent mechanisms, such as the induction of the IL-1 receptor antagonist (24). The antibacterial properties of AAT are primarily demonstrated through its inhibition of Streptococcus pneumoniae in the lungs of mice. A previous study reveals that lung clearance in untreated mice infected with S. pneumoniae is compromised due to the degradation of surfactant proteins A and D (which are important for phagocytic activity) by neutrophil elastase (25). Conversely, AAT was shown to inhibit neutrophil elastase-mediated degradation, thereby alleviating the bacterial infection in the lungs (25). Additionally, AAT exerts antiapoptotic effects on structural lung endothelial cells (26). Previous studies have investigated the role of AAT in disease regulation, particularly in autoimmune diseases, diabetes and cell transplantation (9,27). Furthermore, there is an adaptive immune response to AAT in AAT-deficient lungs (28). In addition, the anti-inflammatory and immunomodulatory properties of AAT remain intact despite its anti-elastase effect (29). AAT therapy can prevent or reverse type 1 diabetes and acute graft-vs.-host disease (GvHD) in preclinical models of autoimmunity and transplantation, in which alterations in cytokine and transcriptional profiles, as well as T cell subset tolerance, are observed (30,31).

AAT may have a role in cellular senescence. Oxidative stress is central to the cellular aging process (32) and the supplementation of exogenous AAT can increase antioxidant levels such as SOD and reduces oxidative stress (33). The balance between oxidants and antioxidants is indirectly restored through the antiapoptotic and anti-inflammatory effects of AAT, although AAT does not directly facilitate the clearance of oxidants. One of the key physiological functions of AAT is to protect lung tissue from serine proteases (34), and AAT specifically inhibits neutrophil elastase, proteinase 3 and proteinase G (35). The identification of AAT as a potent inhibitor of neutrophil elastase led to the proposal of the protease-antiprotease imbalance concept, which links the pulmonary destruction associated with AAT deficiency (AATD) to the unchecked activity of proteases (36). AATD results in the loss of inhibition of neutrophil serine proteases, leading to local tissue damage, as highlighted in the protease-antiprotease hypothesis (37). Furthermore, AATD is associated with the overexpression of inflammatory cytokine, which triggers inflammation in lung cells, resulting in both lung and liver disease.

AATD is an autosomal codominant disorder caused mainly by point mutations in the SERPINA1 gene that can cause lung related diseases such as emphysema (39). Decreased serum and tissue levels of AAT increase the risk of developing COPD and emphysema (7,8). Compared with healthy individuals, patients with COPD, emphysema or bronchiectasis have an increased susceptibility to AATD (15,16). AAT influences exacerbation patterns in patients with COPD, particularly in those with frequent exacerbations of AATD (40). The levels of AAT protein differ across various lung diseases, including cystic fibrosis, interstitial pneumonia and bronchiectasis. In cystic fibrosis, AAT levels remain normal, but neutrophil elastase levels increase to levels that exceed the protective effect (41). Lower serum AAT levels are prevalent in patients with non-idiopathic interstitial pneumonia compared with patients with idiopathic interstitial pneumonia (42). Reduced AAT levels can also instigate bronchiectasis (43). In contrast to COPD, AATD is associated with an increased abundance and activity of primary granule proteins, including neutrophil elastase, on the cell surface (44). Coronavirus disease 2019 represents a novel challenge with an unprecedented impact on human health and development (45). AAT inhibits severe acute respiratory syndrome coronavirus 2 infection by blocking transmembrane serine protease 2 (46).

In addition to the lung diseases mentioned above, AAT is also associated with a poor prognosis for cancer. In non-small lung cancer cell lines, the presence of exogenous AAT inhibits staurosporine (STS)-induced apoptosis. At the same time, CLU (a pro-tumorigenic gene coding clusterin protein) expression was higher (38). Furthermore, the expression of AAT is associated with the metastasis of lung adenocarcinoma cells, potentially promoting their spread by upregulating fibronectin (47). The upregulation of the expression of AAT enhances the adhesion between lung adenocarcinoma cells and human umbilical vein endothelial cells (47). This adhesion represents a key step in the processes of tumor invasion and metastasis.

In summary, AAT is associated with a variety of lung inflammatory diseases. The expression level of AAT is different in different pulmonary inflammatory diseases. The upregulated expression of AAT can inhibit the inflammatory factors produced by lung inflammation, while the lack of AAT can promote the expression of inflammatory cytokines in the lung (Table I).

AATD is associated with neonatal hepatitis, cirrhosis hepatocellular carcinoma and other liver-related diseases (17). Misfolded AAT accumulates in the ER of hepatocytes, leading to mitochondrial dysfunction (48). Defective AAT results in swelling and damage to hepatocytes, which can progress to cirrhosis and pancreatitis (49,50). Hepatic steatosis can exacerbate acute pancreatitis (51) and panniculitis may be the initial presentation of both AATD and pancreatic disease (52). Hepatic steatosis acute pancreatitis is associated with reduced levels of AAT and these levels associate with increased disease severity (51). A previous study indicates that AAT may be effective in treating acute liver failure and pancreatic disease (53). Furthermore, AATD may predispose patients to panniculitis (50). In addition to being associated with a variety of lung inflammatory diseases, AAT is also associated with liver inflammation. The main manifestation of AATD is that it can cause diseases such as hepatitis, panniculitis, cirrhosis and pancreatitis.

AAT exhibits anti-inflammatory and immunomodulatory effects in various lung diseases; however, there is increasing evidence that it also has a role in diseases such as rheumatoid arthritis, systemic lupus erythematosus (9,31,54,55). Autoimmune diseases are characterized by an overactive immune system that attacks the tissues and organs of the host. Numerous mechanisms and factors can trigger these diseases, including the inflammatory response. Consequently, anti-inflammatory therapies hold promise for the treatment of autoimmune diseases. AAT, an anti-inflammatory protein, can prevent and reverse type 1 diabetes and improve conditions such as rheumatoid arthritis and systemic lupus erythematosus (SLE) (9,54). Wegener's granulomatosis (WG), another autoimmune disease, is classified as a necrotizing granulomatous vasculitis. Proteinase 3 is predominant in WG, and AAT acts as the main inhibitor of proteinase 3; thus, AATD may contribute to the pathogenesis of WG (55,56). Furthermore, AAT is hypothesized to be a novel immunomodulator in transplantation (27). Acute graft-vs.-host disease (GvHD) arises from the interaction of donor T cells, host antigen-presenting cells and various proinflammatory cytokines (such as TNF-α and IL-1β). However, exogenous AAT can mitigate clinical manifestations of GvHD (31). Autoimmune diseases are caused by an active immune system that produces a number of antibodies that attack its own tissues, leading to inflammation and tissue damage. In this process, AAT has an important anti-inflammatory role, and AAT has become a potential therapeutic target for immune-mediated inflammation.

AAT is associated with heart disease and neurodegenerative diseases. Plasma-derived AAT reduces cardiac infarct size in mice with acute myocardial infarction (57). Furthermore, exogenous AAT decreases caspase-1 activity in the ischemic myocardium, thereby offering myocardial protection (58). A previous study indicated an association between AAT and the regulation of vascular function by lipoproteins (59). Neuroinflammation contributes to the degeneration of nerve cells, which is a hallmark of neurodegenerative diseases. Blocking neuroinflammation by downregulating inflammasome expression levels by altering the expression of AAT may be beneficial in delaying the onset of neurodegenerative diseases, as demonstrated in rd1 mice, a mouse model for retinal degeneration (60,61).

AAT also exhibits therapeutic potential in diabetes, with its activity being altered in both type 1 and type 2 diabetes mellitus (62). Additionally, AAT protects pancreatic β-cells from cytokine-induced apoptosis (63), with these effects potentially being mediated through the cAMP pathway (64). Upregulation of AAT expression levels reduces the extent of intervertebral disc degeneration (65). In addition, there is a positive correlation between AAT levels and different types of cancer, including pancreatic, ovarian, breast and colorectal cancers (66–69). AAT enhances the resistance of non-small cell lung cancer cells to anticancer drug-induced apoptosis and autophagy (70). Additionally, higher concentrations of AAT are observed in the sera of patients with colorectal cancer compared with healthy controls (66). Patients with gastric cancer also have increased AAT levels in the gastric fluid compared with that of healthy individuals and patients with benign gastrointestinal diseases (71); however, the precise mechanism underlying this observation remains unclear and warrants further investigation. Nonetheless, AAT has a potential use as a biomarker for gastric-related diseases (72) (Table II).

Genetic polymorphisms are associated with disease development and prognosis. The SERPINA1 gene, which encodes AAT, is polymorphic, with >100 known variants (74). Following gene mutation, plasma AAT can undergo three different fates: Intracellular storage, intracellular degradation or lack of synthesis (75). These alterations result in a compromised defense mechanism in the lungs against serine proteases (73). Wild-type AAT proteins exhibit variable folding patterns. A more stable conformation is achieved when the active central loop is incorporated as the fourth strand in β-sheet A. The formation of these more stable conformations can render AAT susceptible to mutations (76). Severely misfolded mutants trigger the unfolded protein response (UPR), which enhances protein folding. Conversely, if these mutants fail to activate the UPR, they can promote NF-κB-mediated ER overload responses (77). The protease inhibitor (Pi) M homozygotes represents the normal genotype, characterized by normal AAT plasma levels (78). Heterozygotes composed of M-type and other phenotypic (S/Z) alleles exhibit AAT deficiency (78). By contrast, the PiZ, PiS and Null alleles are defective variants, with the PiZ allele most frequently associated with severe defects and disease (79,80). Missense mutations identified in the PiZ variant of AAT (Z-AAT) may accelerate misfolding and/or lead to the formation of aggregates (81), resulting in increased N-glycosylation of Z-AAT.

Several studies have identified and characterized new variants of AAT mutants (79,80,82). One such defective variant, Ala336Pro, demonstrates a propensity to polymerize more readily compared with both the wild-type AAT and Z-AAT as it forms the polymerization intermediate more efficiently. Furthermore, the folding barrier for Ala336Pro AAT is notably lower compared with that of Z-AAT (83). Another novel mutant, Trento, has been shown to be secreted from cellular models; however, its conformational stability is compromised (82). By contrast, the Gly349Arg variant, which is part of the AAT response center loop, is classified as a functionally defective (type II) AATD mutant. Although it is secreted normally in cellular models of AATD, it exhibits reduced anti-neutrophil elastase activity. This variant also demonstrates an unfavorable presentation of the RCL to homologous proteases, and the insertion of the RCL into β-sheet A is impaired (84). The diversity of the AAT gene mutants results in various phenotypic characteristics, which are associated with diseases such as AATD (Table III).

Serum AAT regulates ligand-receptor interactions, which in turn modulate cytokine and neutrophil intracellular signaling (85). In vitro, demonstrate that AAT reduces the expression of Superoxide anion (O₂⁻) in neutrophils and inhibits the stimulation of cyclic adenosine monophosphate receptors as well as the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (86). Neutrophil elastase, a serine protease, is a key enzyme produced by neutrophils (87). In patients with AATD, AAT levels are decreased, inactive polymers of AAT are present in the plasma and neutrophil elastase levels are increased, resulting in an imbalance in the pulmonary protease-antitrypsin system (88–91), as shown in Fig. 1. AAT acts as a serine protease inhibitor through RCL. At normal levels, AAT binds to the serine protease and causes aberration and inactivation of the serine protease. If the level of AAT is reduced or the level of serine protease is increased, the inhibitory effect cannot be played, resulting in the occurrence of disease (28,91). In addition, another serine protease, protease 3, is also thought to have the same or even greater impact on the disease process (92).

In addition to directly interacting with proteases, AAT also interacts indirectly with a variety of cytokines. The mechanisms of the innate immunity can be modulated by the anti-inflammatory activity of AAT, which is mediated through interactions at the cell surface (93). AAT inhibits the secretion of proinflammatory cytokines (94). Both native and oxidized forms of AAT inhibit the ATP-induced release of IL-1β from human monocytes (95,96), independent of the antielastase activity of AAT. In addition, AAT regulates ATP-induced IL-1β release through a novel triple transmembrane signaling pathway. This triple transmembrane signaling pathway includes lipid scavenger receptor CD36, calcium-independent phospholipase A2β and the release of a small soluble mediator (96). This mediator activates nicotinic acetylcholine receptors, thereby inhibiting the ATP-induced release of IL-1β from human monocytes (96). In addition, glycosylated AAT binds to IL-8, the ligand for C-X-C motif chemokine receptor 1 (Cxcr1), and obstructs the interaction of IL-8 with Cxcr1, thereby inhibiting the release of pro-inflammatory cytokines (97). In the presence of Z-AAT and AATD, neutrophils remain active and accumulate in the interstitial space, exacerbating connective tissue destruction. It causes macrophages, monocytes, alveolar epithelial cells and endothelial cells to release inflammatory cytokines such as IL-6, IL-8, tumor necrosis factor-α (TNF-α) and C-X-C motif chemokine ligands 8 and 1 (8,95,96,98,99), as shown in Fig. 1. Circulating serine protease inhibitors, including human AAT (hAAT), inhibit the secretion of proinflammatory cytokines IL-17 and IL-6 (100). hAAT has a notable role in inducing the production of anti-inflammatory cytokines. It enhances the expression of IL-1 receptor (IL-1R) in macrophages and human monocytes and promotes distinct phosphorylation and nuclear translocation patterns of p65, a key transcription factor necessary for the expression of IL-1R (101) as shown in Fig. 2. Additionally, hAAT increases the number of T-regulatory cells as well as the expression of C-C chemokine receptor type 6 in animal models (100,102).

AAT is involved in a variety of complex signaling pathways. It attenuates coagulation and inhibits the cytokine-induced activation of JNK and NF-κB in the instant blood-mediated inflammatory response (103). Its anti-inflammatory activity also involves NF-κB-dependent mechanisms (24). The accumulation of the Z-AAT variant activates the NF-κB signaling pathway, leading to the hypothesis that the downstream targets of NF-κB are components of the proteostasis response network in this specific type of proteinopathy (104). Furthermore, the reduction of Z-AAT monomers may stimulate the expression of the PiZ by decreasing the activation of hepatic NF-κB and IL-6 levels (105). Additionally, respiratory epithelial cells induce oxidative stress and activate the NF-κB signaling pathway under senescent conditions (106).

Oxidative stress is implicated in both the physiological and pathological processes of AATD, suggesting that AAT may have a role in cellular senescence (107,108). Additionally, TNF-α is key to the pathogenesis of both hereditary AATD and non-hereditary COPD. TNF-α can induce signal transduction in immune cells and lung endothelial cells, and AAT is a key regulator of the TNF-α signaling pathway (109). AAT inhibits the activity of TNF-α-converting enzyme, suppresses the upregulation of TNF-α receptor 1 and reduces the expression of TNF-α (Fig. 2). Calpain is activated by TNF-α and AAT inhibits calpain activity, leading to a decrease in the level of AAT itself (99). In addition, AAT can inhibit the phosphorylation of IκBα, thereby reducing the activation of NF-κB and inducing target gene transcription (110). In alveolar epithelial cells, lipopolysaccharide (LPS) induces toll-like receptor (TLR) signaling pathways (54,96,111). AAT exerts anti-inflammatory effects by inhibiting the expression of TLR4 and the phosphorylation of IκBα (Fig. 2). This signaling pathway also activates the JNK signaling pathway to produce proinflammatory cytokines (103). However, AAT can inhibit the phosphorylation of JNK and thus inhibits the proinflammatory pathways (103,111). AAT also inhibits the TNF-α induced activation of the WNT/β-catenin signaling pathway in human bone marrow cells (61).

AAT inhibits the apoptosis of non-small lung cancer cells induced by STS (112). STS can induce apoptosis by downregulating the Akt/MAPK pathway. AAT can eliminate this downregulatory effect of STS and thus inhibit STS-induced apoptosis (38). AAT blocks the inhibition of Ser473 phosphorylation by STS, thereby inhibiting apoptosis. STS inhibits the MAPK signaling pathway by inhibiting the phosphorylation of ERK 1/2 and p90RSK (38). AAT is involved in blocking STS action as well as regulating cell proliferation and the transcription of cell survival genes (Fig. 2). AAT may also have a role in the Janus kinase-STAT and T-cell receptor signaling pathways (113), but the specific mechanism of action of AAT requires further investigation.

Numerous studies suggest that chronic non-communicable diseases such as COPD develop as a result of a combination of exposure to various environmental factors (such as smoke, organic dusts, irradiation, toxic agents and metal substances) and genetic predispositions (11,13,115,117–119). Levels of AAT vary under different exposure conditions, and continued exposure of patients with AATD to certain environmental factors accelerates disease progression. There is a complex interrelationship between smoke exposure, circulating AAT levels, systemic inflammation and lung function (120). Furthermore, AAT levels differ between smokers and non-smokers (117). Cigarette smoke has been shown to inhibit AAT uptake in dermal cells and the lungs of mice (10); this inhibition is mediated by neutrophil-derived serine proteases, primarily neutrophil elastase, which can induce connective tissue rupture, leading to alveolar space enlargement and emphysema in animal models (118). Exogenous AAT is protective and can inhibit thrombin and plasma proteins that leak into the lungs following cigarette smoke exposure, thereby preventing protease-activated receptor type 1 activation and the release of MMP-12 and TNF-α, which inhibits matrix degradation (121,122). Furthermore, cigarette smoke acts as a proinflammatory agent (123). In individuals with genetic defects in AAT, exposure to cigarette smoke accelerates the development of COPD, eliciting an inflammatory response from AATD macrophages to cigarette smoke-induced extracellular vesicles (124). This is evidenced by the additive role of smoking and intermediate AAT levels in PiMZ heterozygotes in the development of emphysema (125), suggesting that gene-environment interactions are key in the pathogenesis of COPD (119). AAT may mitigate smoking-induced inflammation and stromal breakdown through an anti-inflammatory mechanism that is associated with the inhibition of TNF-α, providing partial protection against emphysema (126).

Various sources of exposure, including toxic agents, metals and irradiation, notably impact the expression of AAT. Chronic tramadol exposure leads to the dysregulation of α-1-antitrypsin (encoded by SERPINA1b) (11), while exposure to sulfur mustard notably increases AAT levels in saliva (12). In addition, arsenic metalloid exposure in tap water reduces AAT in sputum (13). Irradiation also alters AAT levels; in a mouse model subjected to total body irradiation with 11 Gy of cobalt-60 γ radiation, AAT expression levels were increased compared with that of non-irradiated controls (127,128). Furthermore, upregulation of the AAT precursor expression level was noted in the plasma of CBA/CaJ mice exposed to either 0 or 3 Gy of 137Cs gamma radiation (129). In a low-dose irradiated rat model, established using intratracheal drip injection of uranium tailings suspension, AAT expression levels were similarly upregulated (14). The protective mechanisms of AAT in environmental exposure injuries remain unclear and warrant further investigation.

Occupational dust exposure in patients with AATD also affects lung function (130). Organic dust can induce the production of proinflammatory cytokines in vivo (131). The SERPINA1 PiMZ genotype interacts with outdoor particulate matter and occupational exposure to vapors, dust, gas and fumes, potentially diminishing lung function (116). Furthermore, occupational inhalation exposure has been independently associated with respiratory symptoms and airflow limitation in individuals with severe AATD (132) (Table IV).