The Role of Bioactive Small Molecules in COPD Pathogenesis

Abstract

Chronic obstructive pulmonary disease (COPD) is recognized as a predominant contributor to mortality worldwide, which causes significant burdens to both society and individuals. Given the limited treatment options for COPD, there lies a critical realization: the imperative for expeditious development of novel therapeutic modalities that can effectively alleviate disease progression and enhance the quality of life experienced by COPD patients. Within the intricate field of COPD pathogenesis, an assortment of biologically active small molecules, encompassing small protein molecules and their derivatives, assumes crucial roles through diverse mechanisms. These mechanisms relate to the regulation of redox balance, the inhibition of the release of inflammatory mediators, and the modulation of cellular functions. Therefore, the present article aims to explore and elucidate the distinct roles played by different categories of biologically active small molecules in contributing to the pathogenesis of COPD.

Keywords:

• Bioactive small molecules
• COPD
• pathogenesis

Introduction

Chronic obstructive pulmonary disease (COPD) represents a prevalent heterogeneous disease that is both preventable and treatable, which is characterized by persistent respiratory symptoms and airflow limitation [1]. It is the third leading cause of death worldwide, resulting in 3.23 million deaths, which accounted for 6% of the total deaths in 2019 [2]. A nationwide cross-sectional study revealed that the prevalence of COPD among individuals over the age of 40 was 13.6% (95% CI 12.0–15.2) in China [3]. Despite significant advancements in the treatment of COPD, there remains a huge need for the development of safe and effective disease-modifying therapies. Presently, there are no pharmacological treatment methods available for COPD that can slow disease progression or reduce mortality rates.

Bioactive small molecules constitute a crucial component of the body’s homeostasis and exhibit a wide range of functions, forming complex interaction networks among themselves. These substances include small proteins, active peptides, active amino acids and derivatives, amine compounds, lipid substances, gas signaling molecules, and metal ions. They possess characteristics such as small molecular weight (generally less than 10 Kd), simple structure, and widespread tissue distribution. The respiratory system serves as a vital target organ for bioactive small molecules, as they act on the respiratory system via pulmonary circulation. Conversely, lung tissue can generate various bioactive small molecules, exerting paracrine and autocrine effects. The present article primarily discusses the recent research progress on the roles of different types of molecules [4, 5].

Amino acids and metabolic derivatives

Former understandings surmised that amino acids functioned solely as constituents for protein synthesis and substrates for energy metabolism. However, recent comprehensive investigations have illustrated a different perspective, revealing that individual amino acids and their metabolites exert influence on a multitude of diseases, functioning as neurotransmitters, modulators, and hormone-like biological agents. Furthermore, these amino acids and their derivatives harbor unique biological and physiological effects while also engaging in intricate interplay with one another.

Homocysteine (Hcy)

Homocysteine, as an essential intermediary in the metabolic pathways of methionine and cysteine, assumes a pivotal role. Notably, it cannot be directly obtained from dietary sources and is acknowledged as a multifaceted detrimental factor. Elevated homocysteine concentrations have garnered recognition as a noteworthy cardiovascular risk factor [6]. Contemporary investigations have unveiled several pathways by which homocysteine potentially contributes to the onset and advancement of COPD.

Hcy possesses the potential to disrupt the synthesis of reduced Glutathione (GSH). In the studies by Andersson et al. [7] and Chaudhary et al. [8], the levels of Hcy were notably elevated in COPD patients, while the expression levels of GSH were significantly reduced in comparison to healthy control groups. Moreover, Täger et al. [9] indicated a substantial depletion of GSH in the pulmonary tissues of COPD patients when contrasted with individuals free from the condition. This reduction in GSH levels demonstrated a positive correlation with the deterioration of lung function. GSH serves as a vital antioxidant in the pathogenesis of COPD, responsible for the scavenging of free radicals, maintenance of airway epithelial cell integrity, as well as exhibiting anti-inflammatory and protective effects on the lungs. Hcy has the capacity to compromise patients’ antioxidant ability by inhibiting or interfering with GSH synthesis, thus assuming the role of an oxidative agent involved in COPD-related oxidative stress.

Hcy may stimulate the proliferation of airway smooth muscle, which is acknowledged as a contributing factor to airway remodeling and plays a role in the initiation and advancement of COPD. Investigations have revealed that Hcy exerts concentration-dependent stimulation on the proliferation of airway smooth muscle cells and fibroblasts, subsequently promoting collagen synthesis in fibroblasts. These findings suggest that Hcy might partake in the process of airway remodeling by enhancing the proliferation of smooth muscle cells and fibroblasts, as well as fostering the synthesis of collagen proteins [10, 11].

Hcy has the capability to promote the release of inflammatory mediators. As highlighted by Zhang et al. [12], Hcy stimulates the expression of Chemokine (CC-motif) ligand 2 (CCL2) in vascular smooth muscle cells, subsequently triggering the activation of Protein Kinase C (PKC) and the Nuclear Factor Kappa-B (NF-$\kappa$ B) signaling pathway. CCL2, in turn, facilitates the activation of monocytes and macrophages, thereby inducing the upregulation of inflammatory cytokines such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), and C-X-C motif chemokine ligand 8 (CXCL-8), thereby amplifying local inflammatory responses [13].

Homocysteine impairs NO-dependent vasodilation [14] and induces vasoconstriction [15]. Current research indicates that Hcy induces the release of the inflammatory factor IL-6 by activating NF-kB in VSMCs. It also reduces the synthesis of reduced glutathione and stimulates the proliferation of smooth muscle in the airway, all of which contribute to the development of COPD. However, the exact role of homocysteine in the pathogenesis of COPD remains partially unknown, necessitating further research for a comprehensive investigation.

Taurine

Taurine is an unbound amino acid ubiquitously present in the anatomical structures of animals, with abundant origins that can be engendered via cysteine metabolism or procured directly from nourishment. Taurine encompasses myriad physiological capacities, encompassing antioxidative stress resilience, anti-apoptotic properties, preservation of intracellular calcium equilibrium, and acts as a guardian of cellular integrity and equilibrium of bodily systems. Presently, there exists a restricted body of research pertaining to the role of taurine in the etiology and progression of COPD.

Taurine functions as an essential regulatory factor in modulating oxidative stress, and diminished taurine levels can culminate in a reduction in the activity of respiratory chain complexes I and III [16]. Exposing isolated cardiomyocytes to a medium containing $\beta$-alanine leads to a substantial decrease in taurine levels and a concurrent elevation in mitochondrial oxidative stress. Nevertheless, the co-administration of taurine with $\beta$-alanine effectively mitigates the detrimental impact of $\beta$-alanine on mitochondrial function. Conversely, treating the cells with taurine alone, in the absence of $\beta$-alanine, does not exert any discernible influence on mitochondrial activity, likely due to its limited effect on cellular taurine levels. Thus, taurine acts as a pivotal regulator of mitochondrial protein synthesis, augmenting electron transport chain activity, and safeguarding the mitochondria against excessive superoxide-induced damage [17].

Within an animal model of inhalable Particulate Matter (PM)-induced pulmonary emphysema and airway inflammation, PM-induced decline in C/EBP $\alpha$ protein within bronchial epithelial cells triggers anomalous expression of NADH dehydrogenase gene, eventually fostering heightened autophagy. Notably, the administration of exogenous taurine entirely reinstates mitochondrial gene expression levels, thereby ameliorating PM-induced pulmonary emphysema and airway inflammation [18].

Taurine plays a vital role in maintaining normal cellular function by inhibiting oxidative stress and restoring mitochondrial function to regulate redox balance. However, there is currently limited research on the involvement of taurine in the pathogenesis of chronic obstructive pulmonary disease (COPD). As an important antioxidant bioactive molecule, further investigation is required to elucidate its mechanisms of action and its significance in COPD.

Histidine

Histidine, an indispensable amino acid for optimal nutrition, bestows a multitude of acknowledged health benefits. Nonetheless, under pathological circumstances, there is a tendency for the circulating concentrations of histidine to diminish [19]. Investigations have unveiled that patients with COPD exhibit reduced levels of histidine, creatinine, glycine, and serine in their serum when compared to healthy controls. Notably, histidine manifests a positive correlation with lung ventilation function index, Forced Expiratory Volume in 1 s (FEV1%) pred, while displaying an inverse association with low attenuation area (LAA%) as well as the levels of inflammatory mediators IL-6 and Tumor Necrosis Factor (TNF-$\alpha$) [20, 21]. Furthermore, supplemental histidine improves circulating markers of heightened inflammation and oxidative stress. Moreover, histidine holds promise as a conceivable biomarker [22] for exacerbation of COPD. Exogenous histidine supplementation has demonstrated the ability to curb the production of pulmonary macrophages. Through upregulating the expression of Sirtuin 1 (SIRT1), inhibiting the activation of the inflammatory complex NLRP3, and diminishing the generation of Interleukin-1$\beta$ (IL-1$\beta$) and Reactive Oxygen Species (ROS), histidine likely plays a role in modulating the inflammatory response in COPD by influencing the population and functionality of alveolar macrophages [23]. However, histidine supplementation should be carefully considered as a treatment option owing to few clinical studies performed at present.

N-acetylcysteine (NAC)

The antioxidative properties of N-acetylcysteine have long been acknowledged and reported. Although the oral bioavailability of this medication has not been exhaustively elucidated, its primary role is believed to lie in its function as a precursor of glutathione [24]. Oral administration of N-acetylcysteine leads to deacetylation and conversion to cysteine, resulting in an elevation of reduced glutathione concentration in both plasma and the respiratory tract. This has been demonstrated by the observed increase in glutathione levels in bronchoalveolar lavage fluid following oral NAC administration, as well as the active uptake of glutathione by the lungs from plasma, indicating that the lungs and liver are the primary sites of glutathione synthesis [25, 26]. However, it should be noted that high-dose oral NAC supplementation demonstrated an augmentation of plasma glutathione levels in COPD patients, while no such increase was observed in bronchoalveolar lavage fluid. In vitro animal experiments have validated the ability of N-acetylcysteine (NAC) to safeguard alveolar epithelium from oxidative damage [27, 28]. The free thiol group of NAC can interact with electrophilic residues of reactive oxygen radicals, forming intermediate compounds akin to NAC disulfide [29, 30]. The direct administration of L-cysteine is limited by its low absorption rate in the intestines and rapid hepatic metabolism, whereas oral administration of NAC overcomes these limitations by enabling rapid absorption [31], thereby restoring intracellular glutathione levels that decrease during oxidative stress and inflammation [32–34]. Exogenous NAC can reestablish cellular thiol levels, whereas administration of glutathione fails to achieve a congruent effect [35]. Studies have shown that the effects of NAC in COPD patients are dose-dependent. Increasing the NAC dosage significantly augments reduced glutathione levels, thereby upholding redox balance. Prolonged high-dose usage may effectively regulate the activation of the inflammatory factor NF-$\kappa$B [31] and upregulate the expression of the antioxidant signaling pathway Nrf2, thus exerting antioxidative effects [36].

Recently, there have been several studies investigating the clinical efficacy of NAC. One study found that administering 600 mg of NAC twice daily can effectively reduce oxidative biomarkers in smokers [37]. Additionally, it has been shown to decrease oxidative burden in stable COPD patients [38], alleviate symptoms, and lower the risk of exacerbation in individuals with chronic bronchitis [39]. Another randomized controlled trial conducted with severe COPD patients demonstrated that NAC can improve muscle endurance by reducing oxidative stress [40]. However, a multicenter clinical trial confirmed that NAC does not significantly affect the decline of FEV1 or the frequency of acute exacerbations [41]. It is worth noting that oral NAC requires deacetylation in the gastrointestinal tract to convert into cysteine and serve as a precursor to glutathione. Nonetheless, its bioavailability is limited, which hinders its ability to elevate glutathione levels. Therefore, further large-scale trials are necessary to thoroughly evaluate the role of NAC in COPD treatment.

Active peptides

Active peptides are pivotal in maintaining homeostatic equilibrium within the human body. It is noteworthy that a solitary gene can encode multiple active peptides, each potentially assuming distinct roles in different cells and tissues. Furthermore, post-translational processing can give rise to various modifications of these peptides. Consequently, active peptides showcase many variations, endowing them with intricate functionalities.

Glutamine-Histidine-Lysine tripeptide (GHK)

GHK, a tripeptide composed of the amino acids Glycine, Histidine, and Lysine, is naturally present in human plasma, saliva, and urine, with its levels gradually declining with advancing age [42]. Notably, studies conducted by researchers [43] have demonstrated the ability of GHK to modulate gene expression patterns associated with COPD. A total of 127 genes have been identified to exhibit significant correlations with the severity of emphysema. In individuals with COPD, there is an upregulation of inflammation-related gene expression and a downregulation of gene expression related to tissue remodeling and repair. However, GHK has shown a partial reversal of these gene expression patterns. GHK exerts its effects by activating signaling pathways such as TGF-$\beta$ and Integrin-$\beta$1, which contribute to collagen contraction and remodeling, thereby suggesting its potential involvement in lung tissue regeneration processes [43, 44]. Additionally, GHK has been found to enhance the activity of SOD by inhibiting the activation of p65 and p38MAPK in the NF-$\kappa$B signaling pathway, leading to a reduction in the production of TNF-1 and IL-6 [45]. These findings underscore the anti-inflammatory and antioxidant capacities of GHK, which are integral factors in the occurrence and progression of COPD, involving oxidative stress and chronic inflammation. Further research conducted by investigators [46] has provided confirmation of GHK’s ability to inhibit pulmonary fibrosis, characterized by a decrease in airway collagen deposition, restoration of the MMP9/TIMP-1 balance in the extracellular matrix, partial inhibition of epithelial-mesenchymal transition through the Nuclear factor erythroid 2-related factor 2 (Nrf-2) and TGF-$\beta$1/Smad2/3 phosphorylation pathways, and suppression of airway remodeling [47]. Even though the exact mechanism of GHK’s action is yet to be elucidated, it becomes apparent that the diverse and multiple effects of GHK in COPD can be better understood through its ability to reset the gene pattern back to a healthier state, thereby leading to the activation or deactivation of various cellular pathways.

Calcitonin gene-related peptide (CGRP)

CGRP, a widely distributed neuropeptide, possesses broad-spectrum anti-inflammatory effects, particularly in immune and associated systems [48, 49]. In the lungs, CGRP-like immunoreactivity primarily localizes around nerve fibers in the airway mucosa and in proximity to vascular smooth muscles [50, 51]. It is also present in pulmonary neuroepithelial cells and Clara cells [52, 53]. Due to its unique distribution, CGRP responds to various respiratory stimuli, suggesting its pivotal role in regulating pulmonary circulation [54] and airway hyperresponsiveness [55]. Both neuronal and non-neuronal cells secrete CGRP, indicating its potential involvement in inflammatory lung disorders. Specifically, CGRP is expressed in type II Alveolar Epithelial cells (AEII), which serve as nonspecific immune cells. Under inflammatory stress, the release of CGRP from AEII cells may negatively affect local immune responses. Through autocrine/paracrine pathways, CGRP derived from AEII cells inhibits the secretion of CCL2 and CXCL-8 induced by IL-1$\beta$. This inhibitory effect is achieved by suppressing the phosphorylation and degradation of the inhibitory subunit of NF Kappa B Alpha (I $\kappa$B $\alpha$), thereby inhibiting IL-1$\beta$-induced NF-$\kappa$B activity. Furthermore, CGRP attenuates the generation of ROS induced by IL-1$\beta$. The inhibitory action of CGRP is mediated by elevation of intracellular cyclic Adenosine Monophosphate (cAMP) levels. Augmenting the endogenous secretion of CGRP may exert anti-inflammatory and antioxidant effects by enhancing cAMP levels and suppressing the ROS-NF-$\kappa$ B-CCL2 pathway [56, 57]. However, the mechanism of action of CGRP in COPD is currently unclear. According to current research, CGRP may exert its effects in COPD by inhibiting the secretion of inflammatory factors and through its antioxidant properties, but the specific mechanism remains to be further studied.

Gaseous signal molecule

Gas molecules possess remarkable membrane permeability, enabling them to readily transmit signals through autocrine or paracrine pathways, thereby making them highly active substances involved in sustaining organismal homeostasis. The biological effects of gas molecules primarily arise from their interactions with proteins through diverse mechanisms. These mechanisms encompass the covalent binding of gas molecules to protein metal cofactors, non-covalent binding to pivotal protein domains to modulate protein function, or the occupancy of spatial positions that diminishes the binding of other molecules to the same site. Gas molecules assume significant regulatory roles in the central nervous system, cardiovascular system, respiratory system, cancer, and various other diseases. In this context, our focus is specifically directed toward elucidating the role and intricate interactions of endogenous gas signaling molecules in the respiratory system.

Carbon monoxide (CO)

CO is generated through the oxidation and degradation of ferrous hemoglobin by heme oxygenase (HO), which is an enzyme that occurs in three different isoforme including HO-1,HO-2,HO-3. HO is also located in the endoplasmic reticulum (ER), but likely to NOS, HO is also present in the mitochaondrial. It binds to hemoglobin, forming carboxyhemoglobin, and is transported for gas exchange in the alveoli. In the lungs, CO is displaced by oxygen (O₂) and eliminated from the body [58]. As a gas signaling molecule, CO contributes to cell protection with its anti-inflammatory, anti-apoptotic, and immunomodulatory effects in various diseases. Additionally, CO exhibits vasodilatory properties and inhibits vascular smooth muscle proliferation. Exhaled CO (eCO), akin to exhaled nitric oxide (eNO), has been investigated as a promising respiratory biomarker for both pathological and physiological conditions, encompassing smoking status, pulmonary and other organ inflammatory diseases. The measurement of eCO levels has been explored as a potential approach to assess asthma, stable COPD, exacerbations, cystic fibrosis, pulmonary cancer, or inflammation in surgical or critical care settings. Nonetheless, the specific applications and diagnostic value of eCO as an inflammatory marker remain yet to be fully determined [59]. Some research suggests that inhalation of CO significantly diminishes the expression levels of IL-5, leukotrienes, and prostaglandin E2 in a murine asthma model, indicating its role in inhibiting airway inflammation and protecting against inflammation-induced lung injuries [60]. Furthermore, CO can suppress acute lung injury induced by lipopolysaccharides through the p38 Mitogen-Activated Protein Kinase (p38MAPK) signaling pathway, resulting in reduced release of inflammatory factors (IL-1$\beta$, TNF $\alpha$) from macrophages and increased expression of mitochondrial fusion proteins and anti-inflammatory cytokines (IL-10). Subsequent studies have revealed that CO downregulates the expression of IL-6 in macrophages and lung epithelial cells by modulating the JNK/ERK1/2 pathway, highlighting its antioxidative and anti-inflammatory properties [61, 62]. In addition, CO was prososed to inhibit NOD-leucine rich region-and pyrin domain-containning- 3(NLRP3) inflammasome activation. It achieves this by stabilizing mitochondria, leading to the modulation of mitochondrial reactive oxygen species (mtROS) and inhibition of mtDNA release (see in Figure 1). However, further investigations are necessary to validate the specific mechanisms of action of CO in COPD.

Figure 1. A schematic overview of the role of CO in the pathogenesis of COPD.

Nitric oxide (NO)

NO is generated by the enzymatic conversion of L-arginine to L-citrulline catalyzed by nitric oxide synthase. The nitric oxide synthase family includes neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) isoforms. iNOS and nNOS are predominantly localized in the cytosol, while eNOS is attached to the cell membrane, allowing the extracellular release of NO into the extracellular environment [63]. Fractional exhaled nitric oxide (FENO) exhibits a substantial increase during exacerbation of airway inflammation and is presently widely employed in clinical settings for quantifying the extent of airway inflammation, guiding asthma treatment, predicting exacerbations, aiding in the differentiation of COPD and ACO, and evaluating the response to glucocorticoid therapy [64]. Studies have revealed the association of NO with the pathogenesis and pathophysiology of COPD. Under physiological conditions, NO exerts potent vasodilatory effects on smooth muscles in blood vessels and bronchi, playing a pivotal role in the cardiovascular and respiratory systems. However, under pathological conditions, the excessive production of NO by inducible NOS (iNOS) can lead to heightened extravasation of capillary venous plasma, detachment of epithelial cells, functional alterations, and even cellular death. These processes exacerbate the inflammatory response and contribute to lung injury [65].

Hydrogen sulfide (H₂S)

As the third gas signaling molecule, hydrogen sulfide is endogenously synthesized through the catalytic actions of pyridoxal-5′-phosphate-dependent enzymes, including cystathionine β-synthase (CBS), cystathionine $\gamma$-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MTS). In the context of COPD, endogenous H₂S primarily exhibits protective effects (See in Figure 2). Research has shown that H₂S reduces the production of inflammatory bodies and cell apoptosis, alleviates cellular ferroptosis, and inhibits the release of inflammatory factors by upregulating the expression of the antioxidant transcription factor Nrf2 [66, 67]. Additionally, H₂S inhibits the transforming growth factor $\beta$-1 (TGF-$\beta$1)/Smads signaling pathway, improving lung fibrosis and airway remodeling [68–70]. After epithelial cell damage, epithelial cells can undergo a phenotypic transition known as epithelial-mesenchymal transition (EMT). Exogenous supplementation of H₂S can upregulate the expression of sirtuin 1, modify TGF-$\beta$1-mediated Smad3 transcriptional activation, and subsequently reduce tobacco smoke extract-induced EMT, collagen deposition, and oxidative stress. Moreover, through the activation of sirtuin 1, mitochondrial function is improved, reducing tobacco smoke-induced oxidative stress and cellular aging [71, 72]. Hydrogen sulfide also inhibits EMT by regulating endoplasmic reticulum stress (ERS), reducing ERS markers such as glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and cysteine aspartate protease-12, and decreasing apoptosis in pulmonary arterial endothelial cells [73]. In addition, NaHS inhibits epithelial cell injury and apoptosis by suppressing the PHD2/HIF-1$\alpha$/MAPK, NLRP3-caspase-1, p38 MAPK, and Akt signaling pathways, thereby reducing the generation of pulmonary emphysema and airway inflammation [74, 75]. Recent studies have found that H₂S alleviates tobacco smoke-induced cell pyroptosis by inhibiting the TLR4/NF-$\kappa$B signaling pathway [67].

Figure 2. A simple overview of the pathogenesis of COPD involves the role of H₂S.

In summary, as biologically active small molecules, gasotransmitters exhibit a wide range of physiological activities. They can serve as biomarkers for different disease states in patients with COPD and are extensively involved in its pathogenesis. However, gasotransmitters possess both cytoprotective and cytotoxic effects, which complicates their application. Therefore, further research is needed to explore suitable delivery carriers and safe methods of utilization.

Lipids

Lipids encompass a diverse array of compounds that are extensively distributed throughout the human body. Among them, several types of lipids exist, such as phosphatidylcholine, phosphatidylglycerol, sphingolipids, and fatty acids [76].

Researchers have discovered a close connection between dysregulation of lipid metabolism and multisystem diseases. The preservation of homeostasis in pulmonary surfactant (PS) plays a crucial role in maintaining normal lung function. Investigations have revealed that patients with COPD exhibit diminished expression levels of pulmonary surfactant lipids. In an experimental model of COPD in mice, a significant 60% reduction in pulmonary surfactant lipids was observed, and this decrease in lipids, including phospholipids, cholesterol, and sphingolipids in bronchoalveolar lavage fluid, exhibited a positive correlation with a decline in lung function. In a study conducted by Fritscher et al. [77], quantitative analysis of 25 lipids in the exhaled breath condensate of asthma and COPD patients was performed using tandem mass spectrometry. The results demonstrated elevated levels of prostaglandin E2, leukotrienes, and arachidonic acid in severe asthma and COPD patients, while lipoxins and docosatrienoic acid exhibited reduced levels [78]. Furthermore, smoking impairs the synthesis of dipalmitoylphosphatidylcholine and leads to a decrease of over 50% in phospholipase A2 activity. Smoking also diminishes the expression levels and activity of pulmonary surfactant lipids, resulting in altered adhesion, proliferation, and cell cycle of type II alveolar epithelial cells, thereby causing damage to these cells [79].

Neuroamide

Neuroamide, a notable sphingolipid, holds significance in various biological processes [80, 81]. During the early inflammatory stage of elastase-induced emphysema in mice, neuroamide displays an upregulation that is postulated to contribute to the initial alveolar destruction. However, administering serine palmitoyltransferase inhibitors can effectively decrease the levels of neuroamide, resulting in improved lung function in mice [82]. Neuroamide plays a pivotal role as a mediator in the process of alveolar destruction observed in emphysema, primarily by mediating oxidative stress and apoptosis in the endothelial and epithelial cells within the alveoli. Neuroamide can induce cell apoptosis through various mechanisms, including the activation of kinase inhibitory factors, protein phosphatase 1 and 2 A, as well as tissue proteinase D [83–85]. Furthermore, neuroamide contributes to the generation of oxidative stress by downregulating superoxide dismutase and activating sphingomyelinas (ASMase), thereby resulting in the further accumulation of neuroamide. Ultimately, this process leads to the activation of caspase-3 and subsequent cell apoptosis [86–88]. Additionally, the downstream metabolite of neuroamide, namely Sphingosine-1-Phosphate (S1P), exhibits the potential to alleviate endothelial barrier dysfunction, restore cellular proliferation capacity, and potentially serve a reparative role in the injury inflicted upon alveolar epithelial cells by cigarette smoke [78].

Metal ions

The human body relies on a diverse array of metal ions as essential trace elements. The distribution of these trace elements within the body is subject to influence from immune and inflammatory changes. Many of these trace elements assume pivotal functions in modulating enzyme reactions, either by activating or inhibiting them. They engage in competitive interactions for binding sites with other elements and metalloproteins, thus exerting a profound impact on the delicate balance between oxidative and antioxidant processes, as well as inflammation and various other mechanisms. Moreover, these trace elements can intricately affect cellular membrane permeability [89].

Zinc

Zinc, as a pivotal micronutrient, assumes a crucial role in the growth and development of nearly all known living organisms. It plays a vital part in sustaining cellular, molecular, and systemic biological processes. These encompass fundamental activities like cell proliferation, differentiation, apoptosis, as well as DNA and RNA synthesis. Zinc is further involved in red blood cell production, tissue maintenance, immune function, glucose and lipid metabolism, and intricate cellular signaling pathways [90–92]. Within the pulmonary context, zinc exhibits a notable concentration at the luminal edge of airway epithelial cells, contributing to cellular vitality and exerting anti-inflammatory effects. Chronic exposure to cigarette smoke leads to diminished zinc levels within the epithelial cells, thereby promoting inflammatory reactions and disrupting cellular homeostasis [93]. Smokers with inadequate dietary zinc intake demonstrate a significantly higher prevalence of COPD [94]. It is noteworthy that insufficient zinc intake in the diet is prevalent among COPD patients [95–97]. Nevertheless, the precise mechanisms through which insufficient dietary zinc intake contributes to pulmonary functional impairments in smokers and COPD patients remain unclear. Moreover, numerous studies have established a connection between low zinc levels associated with COPD and cigarette smoke and various factors such as airflow obstruction, oxidative stress, inflammation, cell apoptosis, DNA damage, as well as increased risks of infection, allergies, and cancer [98–102]. One study demonstrated a significant reduction in zinc concentration in the bronchoalveolar lavage fluid of smokers and COPD patients, and this reduction positively correlated with the phagocytic activity of alveolar macrophages. Treatment with the zinc chelator TPEN markedly decreased the phagocytic activity of macrophages, while knockdown of zinc transporters in isolated macrophages from mice resulted in impaired phagocytic function and decreased intracellular zinc levels, thereby emphasizing the important role of zinc transporters in macrophage function [93]. Another study observed that limiting zinc intake in mice exposed to tobacco smoke exacerbated emphysema, suggesting that exogenous zinc supplementation may offer a potential therapeutic approach for COPD. However, the mechanisms underlying how zinc deficiency contributes to the worsening of emphysema are still not well understood. In the future, unraveling the precise mechanisms by which zinc imbalance affects cellular function, redox balance, and inflammation in lung tissue will be of utmost importance [103].

Copper ion

Prolonged exposure to copper (Cu) present in PM2.5 particles contributes to the generation of reactive oxygen species within lung tissue, thereby increasing the incidence of respiratory diseases [104]. Moreover, the severity of exacerbations in COPD is linked to heightened levels of copper (Cu) and the lipid peroxidation product MDA. Serum concentrations of copper and MDA significantly increase in COPD patients [105]. The initiation of copper-induced programmed cell death (known as cuproptosis) participates in the injury of airway epithelial cells in COPD patients. A clinical study reported elevated expression of key regulatory genes associated with copper-induced programmed cell death, including DLD and CDKN2A, in healthy smokers and COPD patients. Additional research demonstrated an elevated copper content in lung tissue and a notable upregulation of these regulatory genes in a COPD rat model. These findings suggest that targeted therapies directed toward copper metabolism-related genes may present a novel approach for COPD treatment [106]. The above studies indicate that copper metabolism disorders may be an important factor in COPD, and gene therapy targeting copper ion metabolism may become a new therapeutic target for COPD. The specific mechanism of copper ion induced COPD needs to be further studied.

Conclusion

Biologically active small molecules play diverse roles in the occurrence and progression of respiratory diseases as important participants in maintaining organismal homeostasis. They are involved in maintaining redox balance, regulating the secretion of inflammatory factors, sustaining cellular vitality, and predicting disease progression. They play a critical role in the onset and severity assessment of COPD. There is a wide variety of biologically active small molecules, each with its own functions, and they are interrelated with each other. Currently, our understanding of the specific roles of biologically active small molecules in the pathogenesis of COPD is limited, and further research is highly needed. By unraveling the specific roles of different biologically active small molecules in the pathogenesis of COPD, we can discover new targets for COPD treatment.

Author contributions

Liao Sha and Yahong Chen contributed to the review design, material collection, anlaysis, interpreation and editing of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work received grants from the National Natural Science Foundation of China (No. 81970037 and No. 82090014).