New approaches to treating chronic obstructive pulmonary disease with Colla corii asini

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death and disability worldwide. Its complex etiology involves factors such as smoking, air pollution, genetic susceptibility, and social environment. With the accelerating global aging population and urbanization, the incidence and burden of COPD continue to rise. Current treatment strategies for COPD are relatively conservative, primarily focusing on bronchodilators, inhaled corticosteroids, and long‐term oxygen therapy. Although these approaches can alleviate symptoms and slow disease progression to some extent, they fail to effectively target the underlying mechanisms of the disease, leaving an unmet clinical need for more‐effective therapies. This highlights the urgency of developing innovative drugs that are both safe and efficacious to address the challenges in COPD treatment. As a traditional Chinese medicine with a long history, Colla corii asini has garnered significant attention for its diverse pharmacological effects and favorable safety profile. Research has shown that Colla corii asini possesses multiple biological activities, including hematopoiesis, nourishing the lungs, enhancing immunity, anti‐infection, antiaging, antitumor, and antifatigue effects. Moreover, it has demonstrated potential in regulating oxidative stress, immune imbalance, and inflammatory responses. Recent evidence suggests that Colla corii asini may play a protective role in lung function through multitarget and multipathway mechanisms. Based on previous research findings, this paper explores the potential therapeutic value of Colla corii asini in COPD treatment by addressing the current clinical management challenges and identifying potential therapeutic targets. It also integrates the pharmacological effects of Colla corii asini into a broader treatment context, providing new perspectives for comprehensive COPD management and laying the theoretical foundation for its modernization and innovative application.

Colla corii asini improves chronic obstructive pulmonary disease (COPD) treatment through anti‐inflammatory, antioxidant, immune‐modulatory, and lung‐nourishing effects, addressing current therapeutic challenges via multitarget mechanisms.

1. CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterized by cough, shortness of breath, and airflow limitation. Even before the COVID‐19 pandemic, COPD was the third leading cause of death worldwide. ¹ , ² COPD is characterized by high prevalence and a chronic course. Patients frequently seek medical attention or require hospitalization due to acute exacerbations and necessitate long‐term treatment, leading to a significant consumption of healthcare resources. ³ The most common causes of COPD are smoking and air pollution. ⁴ COPD has no obvious symptoms or mild symptoms in the early stages. When lung function tests indicate a decline, early drug intervention can effectively improve lung function and quality of life, and reduce the frequency of acute exacerbations. ⁵ In the past, it was believed that if a patient's lung function progressively declined but the symptoms were not severe, the primary intervention was to reduce risk factors, such as smoking cessation ⁶ and vaccination, ⁷ instead of initiating active drug intervention measures. Treatment would typically begin only when lung function was severely impaired and symptoms became more pronounced. However, this approach often misses the optimal window for intervention. In addition, COPD patients are at higher risk of developing other health problems, such as lung infections, ⁸ lung cancer, ⁹ heart problems, ¹⁰ muscle weakness, ¹¹ and certain psychological problems. ¹² It is therefore necessary to intensify the development of drugs suitable for the early treatment of COPD. This is not only associated with alleviating patients' symptoms and improving their quality of life but also with effectively reducing the incidence of acute exacerbations and the use of medical resources. At the same time, the development of new drugs will help fill the gaps in current treatment methods and provide more accurate and comprehensive treatment options for COPD patients.

1.1. Pathogenesis of COPD

After inhaling toxic substances from cigarette smoke or other air pollutants, epithelial cells and macrophages in the lungs can detect these irritants through pattern recognition receptors (PRRs) and initiate an inflammatory response. ¹³ This process activates the NF‐κB signaling pathway through receptors such as TLR4, promotes the expression of inflammatory factors (such as tumor necrosis factor α [TNF‐α], interleukin 6 [IL‐6], and IL‐8), enhances the inflammatory response, and attracts neutrophils and monocytes to migrate to the airways, thereby aggravating the remodeling and tissue damage of the airway wall. ¹⁴ These pathological processes have a significant impact on lung tissue damage and the development of diseases such as COPD. In COPD, IL‐8 attracts neutrophils by binding with CXCR1/CXCR2, and the proteases released by neutrophils, such as elastase, can damage the alveolar structure, ultimately leading to the development of emphysema. ¹⁵ Meanwhile, MCP‐1 recruits monocytes via CCR2, and these monocytes, along with the macrophages they differentiate into, secrete factors such as IL‐1β to sustain the chronic inflammatory state, thereby further exacerbating the inflammatory environment in COPD. ¹⁶ In addition, smoking and pollutant exposure can increase the generation of reactive oxygen species (ROS) through pathways such as NADPH oxidase and mitochondrial dysfunction. ROS can react with proteins, lipids, and DNA, impairing cellular function and damaging lung tissue. In COPD patients, excessive ROS not only damage organelles and activate inflammatory responses but also amplify inflammatory responses by stimulating NF‐κB and AP‐1 signaling pathways. ¹⁷ Chronic smoking or continuous oxidative stress inhibits the activation of Nrf2 in COPD patients, weakening the cellular defense against oxidative damage and leading to a decrease in antioxidant levels in lung tissue. This reduction in antioxidant capacity further exacerbates the damage and inflammatory response caused by ROS, forming a vicious cycle of COPD, and ultimately leading to a continuous decline in lung function and irreversible damage. ¹⁸

1.2. Summary of clinical treatment of COPD

Drug treatment of COPD varies depending on the severity of the disease. Current treatment drugs are mainly classified into bronchodilators, ¹⁹ inhaled corticosteroids (ICS), ²⁰ and phosphodiesterase‐4 inhibitors. ²¹ Bronchodilators include short‐acting β₂‐receptor agonists (SABA), such as salbutamol, ²² which are suitable for rapid relief of acute symptoms; long‐acting β₂‐receptor agonists (LABA), such as formoterol, ²³ which are usually used for long‐term maintenance treatment; short‐acting anticholinergic drugs (SAMA), such as ipratropium, ²⁴ which are generally used for mild symptoms or when rapid relief is required; long‐acting anticholinergic drugs (LAMA), such as tiotropium, ²⁵ which are generally used for long‐term maintenance treatment in patients with moderate‐to‐severe COPD. Inhaled glucocorticoids can be used to reduce the risk of acute exacerbations of COPD. They are usually used in combination with long‐acting bronchodilators (LABA or LAMA). Commonly used inhaled glucocorticoids include budesonide and fluticasone. ²⁶ Roflumilast ²⁷ is a phosphodiesterase‐4 inhibitor that is suitable for patients with moderate‐to‐severe COPD who have frequent acute exacerbations, especially those with chronic bronchitis. It helps reduce inflammation and the number of acute exacerbations.

Traditional Chinese medicine (TCM) treatments for COPD typically focus on methods such as tonifying the lungs and spleen, clearing heat and transforming phlegm, and warming the yang and nourishing the kidneys. ²⁸ TCM is commonly used as an adjunctive therapy during the stable phase of COPD, aiming to alleviate symptoms, enhance physical strength, and reduce the risk of exacerbations. ²⁹ COPD often presents with lung and spleen qi deficiency, and TCM treatments frequently employ herbs that tonify the lungs and strengthen the spleen to enhance immunity and improve respiratory function. Common herbs for tonifying the lungs and spleen include Astragalus, Codonopsis pilosula, Radix Pseudostellariae, Atractylodes macrocephala, Poria, etc. ³⁰ For COPD patients with excessive phlegm, herbs with expectorant and antitussive effects can be used, such as Fritillaria cirrhosa, Apricot kernel, Trichosanthes, Pinellia, etc. ³¹ Herbs that clear heat and detoxify, such as honeysuckle, forsythia, houttuynia cordata, and Radix Isatidis, can help reduce the risk of infection in COPD patients. ³² Common TCM prescriptions for treating COPD based on different syndromes include Baihe Gujin decoction, ³³ which is used for lung and kidney yin deficiency with dry cough and scanty sputum; Shenling Baizhu powder for tonifying the spleen and lung, suitable for patients with spleen deficiency and internal dampness; ³⁴ Pingchuan decoction, ³⁵ which resolves phlegm and relieves asthma and is suitable for patients with shortness of breath and wheezing; Ma Xing Gan Shi Tang, ³⁶ which is used for patients with lung heat and phlegm accumulation, cough, asthma, and excessive sputum.

Colla corii asini (CCA), a traditional Chinese medicine, is derived from the skin of Equidae animals (donkeys) through processes such as bleaching, soaking, depilation, and boiling to form gelatin blocks. People believe that it has the effect of relieving cough and moistening the lungs. Recent studies have reported that CCA exhibits potential in preventing and treating asthma by reducing inflammatory infiltration in patients with asthma. ³⁷ Moreover, it has been shown to enhance both cellular and humoral immunity in mice, suggesting its protective role in the respiratory system. ³⁸ , ³⁹ Previous studies conducted by our research group demonstrated that CCA improve lung function and alleviate pulmonary inflammation in COPD rat model. ⁴⁰ In addition, in the rat lung injury model established by intratracheal instillation of artificial PM2.5 (aPM2.5), CCA can regulate the disordered metabolic pathway induced by aPM2.5 by inhibiting Arg‐1, thereby improving lung inflammation, lung function decline, and lung pathological damage, and has a significant lung function protection effect. ⁴¹

2. PHARMACOLOGICAL EFFECTS OF CCA

By summarizing the pharmacological effects of CCA, it is found that current research focuses on its immunomodulation, antiaging, improvement of lung function, and relief of anemia. The potential effects of CCA in these areas provide important insights for further exploration of its mechanisms in the treatment of COPD. In particular, the immunomodulatory properties of CCA may help alleviate the chronic inflammatory state of COPD patients, whereas its potential to improve lung function lays the foundation for the development of novel therapeutic strategies. A detailed review of the pharmacological effects of CCA is provided below, along with an exploration of its research prospects in the treatment of COPD.

2.1. Pharmacological study on immunomodulatory effect of CCA

CCA has a certain effect of nourishing yin and moistening the lungs. It has obvious therapeutic effects on diseases such as asthma, tuberculosis, bronchitis, and chronic pharyngitis. It has important clinical reference value for the treatment of upper respiratory tract inflammation in combination with other anti‐inflammatory drugs. Liao et al. ⁴² found that under serum‐free conditions, LPS can significantly increase the secretion of IL‐6 and TNF‐α in THP‐1 macrophages, inhibit lipid accumulation in OP9 adipocytes, and increase the secretion of IL‐6. Moreover, both CCA and fish gelatin (FGD) significantly reduced the levels of inflammatory cytokines in macrophages and adipocytes induced by LPS and increased the level of adiponectin secreted by OP9. Fan et al. ⁴³ found that CCA has a protective effect on LPS‐induced inflammatory lung epithelial Beas 2B cells (LILEB 2B cells). CCA can significantly reduce the expression of p‐p65 and p‐IκBα in the NF‐κB signaling pathway associated with LILEB 2B cell apoptosis and its downstream NLRP3, ASC, Caspase‐1, and IL‐1β. It can also reduce the production of mitochondrial ROS in LILEB 2B cells and reverse the changes in mitochondrial membrane potential. This finding may provide a new strategy for the prevention and treatment of acute lung injury (ALI).

In addition to this, Salmonella typhimurium is a foodborne pathogen that can induce inflammatory responses in the intestines of humans and livestock. Ma et al. ⁴⁴ studied the antibacterial effect of CCA ethanol extract (CEE) against S. typhimurium. The study found that CEE showed stronger antibacterial activity than water extract. CEE significantly reduced the expression of invasion proteins SipA, SipB, and SipC at a concentration that did not affect bacterial growth (0.195 mg/mL), and also reduced the messenger RNA (mRNA) levels of related genes. In addition, CEE significantly reduced the ability of Salmonella to invade Caco‐2 cells. In in vivo experiments, CEE reduced bacterial invasion of small intestinal (ileal) tissues in a dose‐dependent manner. This study demonstrated for the first time that CCA has significant anti‐S. typhimurium activity, not only inhibiting bacterial growth but also preventing bacteria from invading host cells by reducing the expression of invasion proteins. This suggests that CCA may be used as a new natural medicine for the treatment of Salmonella infections and related diseases.

Moreover, He et al. ³⁸ used high‐speed centrifugation to separate different components (F0, F1, F2, F3) from CCA and evaluated their potential in immunomodulation and antioxidant effects. The study found that RAW264.7 cells treated with F1 released the highest levels of NO, ROS, IL‐6, and TNF‐α, indicating that it may help to reduce oxidative stress damage. CCA components can also strongly promote the ability of macrophages to phagocytize neutral red, suggesting that they have the potential to enhance the body's immunity.

2.2. Pharmacological study on antiaging effects of CCA

Alzheimer's disease (AD) is an aging‐related degenerative disease characterized by amyloid beta (Aβ) deposition, oxidative stress, inflammation, dysfunction, and cholinergic neuron loss. ⁴⁵ Xiao et al. ⁴⁶ evaluated the antioxidant activity, cell protection, and clearance of Aβ by enzyme‐digested CCA (CCAD). CCAD showed strong antioxidant activity in the oxygen radical absorbance capacity (ORAC) test, especially in samples that had been stored for a long time. Under conditions of cell damage induced by oxidative stress (H₂O₂), CCAD significantly improved the survival rate of PC12 neuron‐like cells, showing a protective effect superior to that of FGD. In addition, CCAD did not affect cell differentiation, indicating that its protective effect would not hinder the normal development of neurons. In the Aβ‐induced neuronal injury model, CCAD significantly reduced the accumulation of Aβ and increased the activity of the degrading enzyme neutral peptidase. In another study, ⁴⁷ CCAD was used in an in vitro three‐dimensional skin model experiment, and it was found that CCAD could significantly accelerate wound healing, suggesting that CCAD may contain active ingredients that promote cell migration and proliferation, which is helpful for skin damage repair. Ultraviolet A (UVA) can induce a decrease in collagen synthesis. The intervention of CCA can help maintain collagen levels, thereby slowing down the photoaging process.

d‐Galactose can induce aging symptoms such as loss of appetite, poor mental state, weight loss, and organ atrophy in mice in a short period of time. ⁴⁸ Wang et al. ⁴⁹ found that CCA can significantly increase the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px) in the serum, brain, and liver of aged mice and significantly reduce the level of malondialdehyde (MDA) in these tissues of aged mice in their study of d‐galactose (gal)‐induced aging model mice. In addition, d‐galactose intervention led to a significant increase in the expression of p16 and p21 in the brain and liver, whereas CCA treatment significantly downregulated the expression of these genes, indicating that CCA may exert its antiaging effect by regulating the expression of aging‐related genes.

2.3. Pharmacological study on improving lung function by CCA

Air pollution, especially fine particulate matter (particles with an aerodynamic mass median diameter of less than 2.5 μm, PM2.5), has become a major environmental issue affecting public health worldwide. Short‐term and long‐term exposure to PM2.5 can cause a series of health problems, especially respiratory diseases. In a previous study by our group, ⁴¹ aPM2.5 was injected into rats' trachea to simulate the damage of PM2.5 to the lungs and observe the potential protective effect and mechanism of CCA. The study found that CCA significantly improved the changes in rat lung function caused by aPM2.5 exposure, including parameters such as expiratory volume, respiratory rate, and ventilation. The lung function parameters of CCA treatment were close to normal levels, suggesting that it helps prevent the decline in lung function caused by PM2.5. CCA significantly regulated the subsets of T lymphocytes. Compared to the aPM2.5 group, the CD4⁺/CD8⁺ ratio in the CCA group increased and the proportion of cytotoxic T cells (CD8⁺) was reduced, indicating that it may relieve lung inflammation by regulating immune balance. It reduced the expression levels of TNF‐α and IL‐1β in bronchoalveolar lavage fluid and increased the level of anti‐inflammatory factor IL‐10. Gene expression level detection also showed that it inhibited PM2.5‐induced inflammatory response. Through metabolomics analysis, the study found that CCA can regulate metabolic disorders caused by aPM2.5 exposure, especially disorders in arginine and nitrogen metabolism and aminoacyl‐tRNA synthesis pathways. CCA can restore the levels of some metabolic markers, showing its protective effect in metabolic regulation.

2.4. Other pharmacological effects of CCA

Blood cells are derived from the proliferation and differentiation of hematopoietic stem cells (HSCs) in the bone marrow. Cyclophosphamide (CTX) ⁵⁰ is a chemotherapy drug that suppresses the immune system. Because CTX is nonspecific for cancer cells, it also damages the stem cell microenvironment, especially the bone marrow. Korean ginseng (KRG) and CCA are traditionally used to enhance the immune system. Rhee et al. ⁵¹ studied the hematopoietic effects of KRG and CCA on CTX‐induced immunosuppressive mice. The study showed that the combination of KRG and CCA at different ratios could improve blood cell counts, promote the recovery of HSC numbers in the bone marrow, and increase the levels of hematopoietic‐related factors in serum. In particular, the ratios of 3:2 and 2:3 had a significant effect on improving T cells and regulatory T cells in the bone marrow and spleen, enhancing cellular immune function. The combination of 3:2 ratio was most effective in restoring bone marrow hematopoiesis, whereas the ratio of 2:3 performed well in spleen immune recovery. The treatment ratio of 2:3 had an effect on the JAK–STAT pathway in the spleen. At a ratio of 2:3, CTX in the JAK–STAT pathway could be restored to inhibit the protein expression of p‐JAK 2, p‐STAT 3, c‐Myc, p‐JNK, and pERK, and significantly inhibited the expression of SOCS 1 increased by CTX treatment. These proteins play an important role in cell differentiation and immune function.

Luo et al. ⁵² found that CCA can significantly increase the hemoglobin (Hb) and serum iron content (SI) in patients with β‐thalassemia during pregnancy in the clinical treatment. Serum ferritin (SF) was not affected. The main component of Hb induced by CCA is adult hemoglobin (HbA). After treatment, the levels of underage adult hemoglobin (HbA2) and fetal hemoglobin (HbF) decreased. This shows that CCA can improve the symptoms of pregnant women with thalassemia and optimize the Hb composition without affecting iron reserves. The Hb level of patients in the treatment group was significantly improved, especially in patients with the βCD41‐42(‐TTCT)/βA genotype. In the effective treatment group, the red blood cell count (RBC) and Hb level were significantly increased. Two genes (ZNF471 and THOC5) were consistently upregulated in the effective treatment group. ZNF471 may regulate gene transcription through the KRAB zinc finger protein (KRAB‐ZFPs) pathway. THOC5 is part of the THO complex and is related to RNA transcription and output. CCA may promote the synthesis of globin by regulating the amino acid transport and ribosome binding of tRNA and improve the stability of erythrocyte membrane and prolong the life of erythrocytes. Patients with βCD41‐42(‐TTCT)/β A genotype respond best to CCA treatment, which indicates that the treatment effect may be genotype‐dependent in the clinical treatment of patients with β‐thalassemia during pregnancy.

In the clinical treatment of ulcerative colitis (UC), Lu et al. ⁵³ evaluated the efficacy of different doses of rectal administration of Panax notoginseng and CCA suppositories and their effects on the body's immune function and recurrence. The study found that for patients with UC, rectal administration of P. notoginseng and CCA suppositories had a positive effect on their inflammatory factors, immune function, UC severity, clinical symptoms, and recovery. In addition, the higher the dose, the better the efficacy, and there was no increase in adverse events.

2.5. Clinical research on CCA

We found that there are currently five ongoing clinical trial projects on CCA on the China Drug Clinical Trials Registration and Publicity Platform (www.chinadrugtrials.org.cn). All these five items come from Dong E E Jiao Corporation Limited, namely Runzao Qingfei paste (CTR20180010), Guilu Erxian oral liquid (CTR20180009; CTR20180006), and Huanglian‐Ejiao capsules (CTR20131690; CTR20131686). The indication of Runzao Qingfei paste is cough caused by acute tracheobronchitis and acute exacerbation of chronic bronchitis. The drug is currently in Phase II clinical trials, and its specification is 60 g/bottle. The indications of Guilu Erxian oral liquid are spermatorrhea (kidney yang deficiency syndrome) and psychological erectile dysfunction (kidney yang deficiency syndrome). Huanglian‐Ejiao capsule is indicated for chronic insomnia caused by yin deficiency with hyperactivity of fire and chronic primary insomnia.

3. EXPLORATION OF THE POTENTIAL MECHANISM OF CCA IN RELIEVING COPD

The primary therapeutic goals for COPD are to alleviate inflammation, ⁵⁴ improve airway function, ⁵⁵ prevent exacerbations, ⁵⁶ and repair tissue damage. ⁵⁷ The possible potential therapeutic mechanism of COPD disease is shown in Figure 1.

FIGURE 1.

Possible potential therapeutic mechanisms for COPD disease.

3.1. Targeting the miR‐21/SATB1/S100A9/NF‐κB axis and CCA intervention to alleviate inflammation in COPD

Hansbro et al. ⁵⁸ have identified the pathogenic role of the miR‐21/SATB1/S100A9/NF‐κB axis in COPD and defined miR‐21 as a therapeutic target for the disease. NF‐κB plays a central role in the inflammatory response of COPD by promoting the expression of inflammatory cytokines such as TNF‐α, IL‐6, and IL‐8. In addition, in our research, we established a COPD mouse model using cigarette smoke extract (CSE) combined with LPS and monitored the progression of the disease by various indicators. After 8 weeks of CCA intervention, we found that CCA significantly reduced the level of TNF‐α in the bronchoalveolar lavage fluid of COPD mice and increased the anti‐inflammatory cytokine IL‐10.

3.2. CCA‐induced NO release: A potential mechanism for alleviating airway smooth muscle constriction and COPD‐related inflammation

Targeting airway smooth muscle relaxation is the key strategy to alleviate airflow limitation. Endothelium‐dependent relaxation mediated by nitric oxide (NO) has been demonstrated in the pulmonary arteries of animals and humans. ⁵⁹ He et al. ³⁸ found that CCA extract induced high levels of NO release from RAW264.7 cells, suggesting that CCA can regulate the NO signaling pathway to promote airway dilation. As a potential regulator, CCA may not only act on airway smooth muscle, but also further alleviate COPD‐related inflammation and oxidative stress through the anti‐inflammatory and antioxidant properties of NO.

3.3. The dual role of CCA in regulating mitochondrial autophagy and oxidative stress in COPD progression

Oxidative stress plays an important role in the occurrence and progression of COPD. Togawa et al. ⁶⁰ found that ROS‐related signaling may contribute to the development of new COPD drugs. Kuwano et al. ⁶¹ found that the accumulation of mitochondrial damage caused by cigarette smoke (CS) is closely related to the pathogenesis of COPD. Mitophagy plays a crucial role in the clearance of damaged mitochondria and is controlled by the PINK1 (PTEN‐induced putative protein kinase 1)‐PRKN (parkin RBR E3 ubiquitin ligase) pathway. In vitro experiments found that overexpression of PRKN was sufficient to induce mitophagy during CSE exposure, thereby reducing mitochondrial ROS generation and cellular senescence, even in the presence of reduced PINK1 protein levels. There are conflicting reports regarding the role of mitophagy in the progression of COPD. Liao et al. ⁴² found that CCA can reduce the production of mitochondrial ROS in LILEB 2B cells and reverse the changes in mitochondrial membrane potential. He et al. ³⁸ found that RAW264. 7 cells induced by CCA extract released the highest level of ROS. On the one hand, CCA may reduce oxidative stress and inhibit cell damage by reducing ROS levels and stabilizing mitochondrial function; on the contrary, in certain cell environments, the ROS generation induced by CCA may participate in regulating cell signaling pathways and promote mitochondrial autophagy to remove damaged mitochondria, thereby restoring intracellular homeostasis. Therefore, it is necessary to further explore the mechanism of action of CCA in different cells and pathological environments, especially in the COPD model, to clarify its bidirectional regulatory effects on mitochondrial autophagy and oxidative stress and its potential therapeutic significance.

3.4. CCA regulation of Nrf2 signaling pathway and antioxidant enzyme expression in COPD treatment

Nrf2 is a key regulatory factor in antioxidative stress. Nrf2 activation can promote the expression of antioxidant enzymes such as SOD and HO‐1, thus reducing oxidative damage. ⁶² Ferrer et al. ⁶³ found that COPD patients showed reduced expression of extracellular superoxide dismutase (EC‐SOD) in the lung interstitial. Wang et al. ⁴⁹ found in a study of d‐galactose (gal)‐induced aging model mice that CCA could significantly increase SOD in the serum, brain, and liver of aged mice. Therefore, CCA may promote the expression of SOD by regulating the Nrf2 signaling pathway, thereby enhancing antioxidant capacity and reducing the damage of oxidative stress to the lung tissue. This mechanism suggests that CCA may have certain potential in the treatment of COPD, especially in pathological stages related to oxidative stress. However, due to the complex pathological environment in COPD patients, the regulatory effect of CCA on Nrf2 and its downstream antioxidant enzymes may vary at different stages of disease progression. Therefore, further investigation of the role of CCA in COPD models and its specific association with the Nrf2 signaling pathway will help clarify its potential therapeutic effects and provide a basis for the development of new therapies based on antioxidative stress.

4. REGULATORY CHALLENGES AND LIMITATIONS OF CCA

Although current research has clarified the pharmacological mechanism of CCA to some extent and predicted its potential application prospects in the intervention of diseases such as COPD, its clinical transformation still faces many practical challenges. As a traditional Chinese medicinal material with a long history, CCA has a complex production process and diverse sources of raw materials. The composition and efficacy of different batches fluctuate greatly, posing challenges to product standardization and supervision. There are many brands in the current market with varying quality, and adulteration occurs frequently, which not only harms the rights and interests of consumers but also increases the difficulty of supervision. Therefore, it is urgent to establish a unified quality standard system, strengthen raw material traceability, processing specifications and ingredient testing, while improving the traceability mechanism and cracking down on counterfeiting to ensure product safety and public trust. In addition, because CCA is highly dependent on donkey skin as raw material, ⁶⁴ the cost is relatively high, and the price remains high, which also affects its universality and accessibility to a certain extent. Although CCA has always been regarded as a relatively safe tonic medicine, its potential risks cannot be ignored. ⁶⁵ For people with allergies, pregnant women, and individuals with specific diseases, the use of CCA may cause adverse reactions, especially when used in combination with modern drugs, and possible drug interactions should be carefully evaluated. ⁶⁶ In addition, although CCA is widely used for its nourishing effects, if people rely too much on it to improve their health, or even use it as an alternative treatment, they may ignore the fundamental role of scientific medical methods and healthy lifestyles in disease prevention and management, thus leading to misunderstandings in health management. Although according to TCM theory, CCA is commonly used to tonify Qi and nourish blood, nourish yin and moisten the lung, its efficacy in modern diseases—especially complex conditions such as COPD—still lacks support from large‐scale, randomized controlled clinical trials. Most existing studies are limited by small sample sizes or observational designs, making the current evidence insufficient to support the broad integration of CCA into modern medical practice. Moreover, for major conditions, such as cancer and cardiovascular disease, CCA cannot yet replace standard therapies established in modern medicine.

5. SUMMARY AND OUTLOOK

In summary, CCA shows promising potential for the treatment of COPD through the synergistic effects of multiple mechanisms. First, CCA may improve airway smooth muscle function and promote airway dilation by regulating the NO signaling pathway, effectively relieving COPD symptoms. Second, CCA can reduce the level of ROS, improve mitochondrial function, and mitigate oxidative stress–induced cellular damage, while simultaneously inhibiting the inflammation triggered by oxidative stress. In addition, CCA may activate the expression of antioxidant enzymes, such as SOD and enhance antioxidant, capacity by activating the Nrf2 signaling pathway, thereby fundamentally alleviating the damage of oxidative stress to lung tissue. These multifaceted mechanisms suggest that CCA could play a key role in a comprehensive COPD treatment plan, offering a scientific foundation for the development of novel natural therapies.

As a valuable component of TCM, CCA has gained wide attention in recent years for its potential in improving low lung function, especially COPD. At present, CCA is available in various convenient forms, including oral liquid, CCA cake, and CCA capsules, which enhance daily usability. Modern scientific formulations have expanded its applicability, boosting market acceptance and patient adherence. Future research should focus on the separation of the main active ingredients of CCA and the analysis of its pharmacological mechanism, clarify its specific of anti‐inflammatory, antioxidant, and immunomodulatory effects so as to provide a scientific basis for the precise treatment of COPD. In addition, it is necessary to strengthen the mechanism research of the combined application of CCA with other drugs, reveal its synergistic effect, optimize the combined medication scheme, and improve the clinical efficacy. At the same time, it is necessary to develop more efficient and convenient dosage forms in combination with modern drug delivery technology, and verify its efficacy and safety through large‐scale clinical studies to accumulate evidence‐based medicine. By combining TCM with modern medicine, CCA aims to create a new method of TCM in the treatment of respiratory diseases.

AUTHOR CONTRIBUTIONS

Wenchao Zhang: Investigation; writing – original draft. Siman Sun: Writing – original draft. Xiaoyu Fan: Conceptualization; writing – review and editing. Jiuming He: Writing – original draft. Qing Li: Writing – review and editing. Hongtao Jin: Funding acquisition; writing – review and editing.

FUNDING INFORMATION

This study was funded by the National Natural Science Foundation of China, grant/award numbers: 82074104 and 8247143489; the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, grant/award number: 2022‐I2M‐2‐002.

CONFLICT OF INTEREST STATEMENT

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

ETHICS STATEMENT

Not applicable.

Zhang W, Sun S, Fan X, He J, Li Q, Jin H. New approaches to treating chronic obstructive pulmonary disease with Colla corii asini . Anim Models Exp Med. 2026;9:50‐58. doi: 10.1002/ame2.70077