Traditional Medicinal Plants Conferring Protection Against Ovalbumin-Induced Asthma in Experimental Animals: A Review

Introduction

Asthma, one of the chronic inflammatory airway diseases, which affecting 300 million people worldwide and is expected to be nearly 400 million by the next 5 years. The incidence of asthma is high and accounting for 1 out of 250 deaths worldwide.¹ Majority of the asthma treatment (as recommended by the Global Initiative for Asthma), target to reduce the symptoms via ameliorating the inflammatory processes.^2,3 To date, current asthma therapies are mainly based on pulmonary, followed by oral or intravenous administrations. The drugs of choice include beta-adrenoceptor-2 (β2) agonists, corticosteroids as well as xanthines and their derivatives. For symptomatic relief from asthma β2 agonists are often the drugs of choice.^3,4 Nevertheless, given the wide choices of available anti-asthmatic drugs, they produce numerous side effects, comprising headaches, nausea and convulsions (xanthines),⁵ cardiovascular effects (β2 agonists),⁶ vomiting (phosphodiesterase type 4 inhibitors),^7–9 osteoporosis, myopathies, adrenal suppression and metabolic disturbances, which may compromise the patients growth especially in young children (corticosteroids).^5,7,10,11

Traditional medicine encompasses the total skill, knowledge and practices used in the maintenance of health as well as in the prevention, diagnosis, enhancement, or treatment of physical and mental illness which can be based on myths, perceptions, and experiences indigenous to various cultures.¹² The use of traditional medicinal plants (TMPs) as herbal medicines which have good potential for treating physiological disorders like asthma or as an adjuvant to modern therapy has been extensively reported since ancient times. In addition, ethnopharmacological studies have been considered as an important tool for bioprospecting new bioactive compounds from medicinal plants.¹³ Although significant progress has been achieved in the synthetic chemistry that involves the synthesis of new molecules, drugs or active constituents developed from medicinal plants are until preserved.^14,15

Traditional herbal medicine is often referred as “complementary and alternative medicine” which includes traditional Chinese medicine, traditional Indian medicine (Ayurveda), traditional Japanese medicine (Kampo) and traditional Korean medicine which are the most widely used systems today. Since all these traditional systems utilise medicinal plants and have been practiced for hundreds or even thousands of years all over the world, some have morphed into orderly regulated medicine systems.^16–18 Nevertheless, to date, there is a lack of information on the use of TMPs as well as their experimental evidences.

Rural individuals from developing countries tend to have more trust in traditional herbal medicine due to their considerable experience and lack of access to modern medicines. Hence, in-depth information on traditional and ethnomedical perspectives can facilitate community-centered approaches under the present medical system given that the potential of traditional herbal medicines in the treatment of asthma is not fully utilized. Thus, established preclinical studies are needed. Several experimental animal models for asthma are accessible for preclinical screening. Among them, OVA-induced asthma animal model has been widely used.

OVA is the main protein found in egg white, which is not intrinsically immunogenic and therefore have to be injected into the systemic circulation in the presence of adjuvants (substances that increase the immunogenicity of an antigen) typically aluminium hydroxide (Alum).¹⁹ Immunization of OVA along with alum in animals induces T helper (Th) cell (preferably Th2) responses, ie, called sensitisation. Further, immunization of OVA to the sensitized animals synergize the former immune responses, ie, called challenge. Subsequently, challenged animal’s exhibit many of the features seen in asthmatic individuals including inflammation, infiltration of eosinophils, production of Th2 cytokines, increase in serum IgE and airway hyper-responsiveness (AHR). OVA challenge models have been long-established to be worthwhile for the preclinical assessment of potential therapeutic agents for asthma, where specific questions regarding allergic asthma can be addressed.

To gain insight into the potential role of natural products, an overview of various traditionally used medicinal plants against asthma and OVA-induced asthma models has been represented here. The attempt has been made to outline the summary of information gathering the anti-asthmatic potential of medicinal plants against OVA-induced asthma and correlated with their traditional use was performed. This review provides a significant contribution to bridging these evidence gaps, creating a resource for safe and effective implementation of TMPs among the communities, confirming their pharmacological activities, potential efficacies and safety as an alternative medicine for asthma treatment.

Methods

In this review, relevant studies were collected from several scientific databases, including PubMed, Scopus, Google Scholar and ScienceDirect (between 2011 and to date). The keywords used for the search include “Traditional herbal medicine” OR “Traditional Indian medicine” OR “Ayurveda” OR “Traditional Chinese medicine” OR “Traditional Korean medicine” OR “Traditional Japanese Medicine” OR “Kampo” OR “Herbal medicine” OR “Natural products” OR “Medicinal plants” OR “Plant extract” AND “Asthma” AND “Ovalbumin” AND “OVA” AND “OVA-induced allergic asthma” AND Anti-asthmatic AND “OVA-induced lung inflammation”. Studies apart from English language and those that does not have full article were excluded from this review. The medicinal plants studied for OVA-induced asthma model, but without supporting any traditional use related to the management and treatment of asthma has been omitted. After applying the inclusion and exclusion criteria’s and eliminating the duplicates from one to another database, a total of 27 TMPs and two polyherbal extracts investigated against OVA-induced asthma model along with its supportive evidence on its traditional use against asthma or its related inflammation were included in the present review.

Anti-Asthmatic Potential of TMPs Against OVA-Induced Asthma in Animals

Animal Model of OVA-Induced Asthma

The use of an appropriate animal model of allergy can help unravel unanswered questions in human allergic diseases.^20–23 Therefore, the following ideal characteristics should be considered for any allergic asthma animal model.

• Induced allergic parameters, both clinical and immunologic reactions, should mimic humans.
• Animal model of allergy-induced asthma by protein antigen alone is ideal, rather than in combination with adjuvants.
• The animal model should be less complicated, with a limited number of sensitisations.
• An ideal animal model serves as a powerful tool for understanding the immunopathogenic mechanisms of the various drug candidates.

Among the different species, mouse models are preferred in allergen-induced studies when compared to rat models.²⁴ Although various other mouse models (C57BL/6 and A/J strains) are available, interestingly, BALB/c mice model, which have a high tendency of developing allergic responses, has been widely used.²⁵ The foremost reason for the high allergic responses is due to the Th2 phenotype where BALB/c mice easily develop Th2-biased immune response. In addition, BALB/c successfully develops clinical symptoms, which are relatable to humans, including infiltration of leukocytes, airway inflammation and wall remodeling (goblet cell hyperplasia or metaplasia, epithelial hypertrophy, epithelial basement membrane thickening), mucus secretion, total and allergen-specific serum IgG1 and IgE, cytokine profile, among others.²⁶ As an example, BALB/c mice sensitised with the insect allergen (Forcipomyia taiwana [biting midge]) show a similar type of eosinophil and lymphocyte infiltrations observed in humans.²⁷ Furthermore, BALB/c mice model can also be used for exploration of novel mechanisms independent of cytokines (IL-4 and IL-5) in allergic airway hyperreactivity.²⁸ In addition, many studies have confirmed the utility of BALB/c mice as a model for allergy.^24,29–31 Having said that induction of allergen-specific hypersensitivity reactions are also species- and strain-dependent,^31,32 indicating that a balance of these factors are required when selecting the best model.

Pathophysiology of OVA-Induced Asthma

Despite different pathophysiological mechanisms in allergen-induced asthma, OVA-induced classical eosinophilic asthma is common. Moreover, OVA in combination with endotoxin (lipopolysaccharide, LPS) at different sensitisation and challenge schedules were used to induce neutrophilic and mixed-granulocytic asthma.^23,33 Although OVA at high doses is sufficient to induce asthma, the use of endotoxin and/or adjuvant can help exacerbate the OVA-induced immune response. For this, several sensitisation and challenge (acute or chronic) protocols have been developed and used. The use of the endotoxin (LPS) and adjuvant (Alum) may overcome the tolerogenic issues of OVA. Moreover, the use of endotoxin in the protocols are preferred in studies focusing on acute neutrophilia. Similarly, an adjuvant such as Alum, in particular, can be used to induce acute asthma models. Of note, Alum induces Th2-biased immune responses, thus synergising and facilitating OVA-induced immune response (Figure 1). Nevertheless, the inclusion of an adjuvant is not necessary for some type of allergy models such as food-induced allergy models.

Figure 1 Pathophysiology of OVA-induced asthma. OVA-induces different types of allergic asthma, including eosinophilic, neutrophilic, and mixed-granulocytic asthma. Although different sensitisation and challenge protocols has been used, the underlying mechanism is nearly similar. Dendritic cells (DCs) are the first innate immune cells encounters the allergen after crossing the respiratory epithelium. DCs process and present the antigen to the CD4+ T cells, which subsequently polarized into Th2 cells via Th2 inducing factor (IL-4). Th2 cells secrete copious amounts of cytokines (IL-4, IL-5, and IL-13), which later activate the naïve B cells to antigen-specific B cells (class switching). Further, antigen-specific B cells secret IgE, which sequentially recognized by the FcεRI on the mast cells and basophils. This process is called sensitisation. Upon re-exposure, allergen experienced leukocytes accelerate the priming process and activate mast cells and basophils. In addition, sensitized mast cells and basophils directly recognize the IgE antigen conjugates and undergo degranulation, which releases vasoactive amines (histamine), lipid mediators (prostaglandin, leukotrienes), chemokines, and other cytokines. As a net effect, the former mediators recruit the eosinophils and neutrophils, induce the mast cell differentiation, hypersecretion of mucus, Th1 cell activation, lung epithelial cells apoptosis, and others.137 Of note, few protocols use LPS or Alum, which accelerate the process, to induce a specific type of allergic condition. The figure was created with the support of https://biorender.com under the paid subscription.

In summary, OVA-induced asthma animal models have been used for 1) classification of allergen types, 2) assessing the efficacy of novel vaccine adjuvants, 3) understanding the molecular mechanisms of different types of allergies, and 4) evaluating potential drug candidates. All the above categories are based on pathophysiological observation, including allergen-specific IgE estimation, anaphylactic symptoms, blood histamine levels, immunophenotyping of mast cells and other subtypes, splenocyte cytokine profiles and histology.

Selective TMPs Conferring Protection Against OVA-Induced Asthma

All the medicinal plants reported in this review have been traditionally used to treat asthma or its related inflammation. Table 1 summarises the details on the family, distribution, traditional uses and chemical constituents of TMPs and two polyherbal extracts. In this review, the data for 27 TMPs and two polyherbal extracts useful against OVA-induced asthma models as well as their potential mechanism of actions are described later.

Table 1 Information About TMPs Conferring Protection Against OVA-Induced Asthma

The treatment with ethanolic extract of Scrophularia striata (S. striata) to asthmatic mice shown suppressed Th2 cytokines (including IL-4 and IL-5) in bronchoalveolar lavage fluid (BALF) and inflammatory cells. In addition, it also decreased the level of total immunoglobulin E (IgE) and OVA-specific IgE in serum.³⁴ These results make evident that S. striata extract have good potential in modulating Th2 cytokines and therefore, can be utilised as an immunomodulatory agent for allergic asthma. Almohawes and Alruhaimi³⁵ reported that of hydro-alcoholic extract of Lavandula dentata (L. dentata) reduced the serum levels of IgE, triglycerides, total cholesterol and glucose in guinea pig with OVA-induced asthma model. Moreover, it also attenuated the levels of malondialdehyde (MDA) and restored the glutathione (GSH) levels in the lungs tissue. These results indicate that L. dentata extract ameliorates asthma and the oxidative stress as induced by OVA.

The protective effect of 50% ethanolic extract of Pistacia weinmannifolia (P. weinmannifolia) root (EEPWR) on inflammation and hypersecretion of mucus in respiratory tract in BALB/c mice was studied by Lee et al.³⁶ Treatment with EEPWR decreased the eosinophil count and Th2 cytokines (IL-4, IL-5 and IL-13) levels in the BALF of OVA-exposed mice. Moreover, EEPWR inhibited total and OVA-specific IgE levels in serum. Additionally, EEPWR also efficiently inhibited the accumulation of inflammatory cells into the lungs, as well as respiratory tract mucus hypersecretion. Moreover, the monocyte chemoattractant protein-1 was significantly reduced following EEPWR treatment in the BALF of OVA-exposed mice. The protective effects of EEPWR on OVA-induced inflammation of respiratory tract were accompanied by the downregulation of mitogen associated protein kinases and activation of nuclear factor-κB. Overall, the studies indicate that EEPWR is a valuable armamentarium for asthma treatment.³⁶

The anti-inflammatory and immunomodulatory activity of hydro-ethanolic extract of Ocimum basilicum (O. basilicum) leaves in OVA-challenged rats were examined by Eftekhar et al.³⁷ Administration of O. basilicum extract decreased the levels of IL-4, IgE, phospholipase A2 and total protein and increased interferon-γ (IFN-γ)/IL-4 ratio in OVA-challenged rats. Additionally, O. basilicum extract showed improvements in OVA-induced changes in immunological, pathological and inflammatory markers in OVA-sensitised rats. The results were comparable and can even be more potent than that for standard dexamethasone, suggesting its therapeutic potential in asthma.

The anti-inflammatory actions of an ethanolic extract of Polyscias fruticosa (P. fruticosa) leaves in OVA-induced asthma was tested by Koffuor et al.³⁸ Administration of P. fruticosa extract reduced the OVA-induced elevation of white blood cells (WBC) and C-reactive protein to normalcy. Moreover, administration of P. fruticosa extract reduced the rate of erythrocyte sedimentation. In the recent study, OVA-sensitized BALB/c mice were treated with ethanolic extract of aerial parts of Herissantia tiubae (H. tiubae) 1 day before evaluating the anxiety and respiratory parameters. Increase in plasma IL-13, which was restored with the treatment of H. tiubae extract was observed. Additionally, there was a rise in total BALF cell count with prominent eosinophilia has been seen. It was determined that H. tiubae extract can show similar action on respiratory parameters to that of aminophylline and behavioral changes as that of diazepam. Suppression of inflammation was as efficient as that for dexamethasone.³⁹

The effects of aqueous extract of Solanum xanthocarpum (S. xanthocarpum) on respiratory tract inflammation and oxidative stress in experimental asthmatic rats were assessed by Gulati.⁴⁰ The administration of S. xanthocarpum extract (50 mg/kg), reduced the levels of blood and BALF OVA-specific IgE in Ova-immunised rats by 37% and 20%, respectively. These effects were comparable with prednisolone (10 mg/kg), which reduced IgE level by 43% and 31% in blood and BALF respectively. Similarly, administration of S. xanthocarpum extract at the dose of 100 mg/kg attenuated the levels of tumor necrosis factor-α (TNF-α), IL-6 and IL-4 and elevated the levels of IFN-γ when compared with control. These data indicate improved immunostimulatory/immunomodulatory effects. In addition, administration of S. xanthocarpum extract (100 mg/kg) ameliorates oxidative stress in the animals and it is indicated by reduced MDA levels and elevated GSH levels. It was hypothesised that the beneficial effects of S. xanthocarpum in bronchial asthma are attributed to the balancing influence on pro-oxidant-antioxidant status and reduction in airway inflammation.

The effect of 70% ethanolic extract of Crocus sativus (C. sativus) flowers on differential and total WBC count in lung lavage fluid of Ova-sensitised rats were reported by Mahmoudabady et al⁴¹ C. sativus extract treatment decreased percentage of neutrophils and eosinophils and total WBC count and the in OVA-sensitised animals. Therefore, the findings indicated that C. sativus extract is effective in alleviating lung inflammatory cells in experimentally induced asthmatic animals.⁴¹ Bulani et al⁴² reported the effect of methanolic extract of Calotropis gigantea (C. gigantea) root on OVA-induced asthma in rats. C. gigantea extract-treatment showed significant inhibition of neutrophil, lymphocyte, eosinophil and total leukocyte count in BALF of animals treated with OVA. Moreover, C. gigantea extract reduced the oxidative stress in OVA treated animals and it was evident by reduced nitric oxide (NO) levels in BALF and lipid peroxidation (LPO) in the lungs and restored levels of GSH, superoxide dismutase (SOD) in lungs. C. gigantea extract also significantly improved the OVA-induced histological changes. These results suggest the potential effect of C. gigantea in OVA-induced asthma.

The anti-asthmatic and antioxidant activities of aqueous extract of Urtica dioica (U. dioica) leaves in OVA-sensitised rats were examined by Zemmouri et al⁴³ The aqueous extract of U. dioica leaves significantly inhibited serum eosinophilia (by 60%), leucocyte (by 32.75%) and lymphocytes (by 29.22%) in BALF of asthmatic rats. Besides, LPO generated following allergen administration was significantly diminished by U. dioica treatment in the lung tissues (by 48.58%), thus confirming that U. dioica aqueous leaves extract confer some protective effects against airway inflammation. Khan and Imtiyaz⁴⁴ reported the ethanolic extract of Wrightia tinctoria (W. tinctoria) leaves treatment decreased leukocyte count when compared to OVA-induced animals. The findings indicate that ethanolic leaves extract of W. tinctoria possess some anti-asthmatic effects, possibly mediated via inhibition of histamine release.

The administration of Asparagus cochinchinensis (A. cochinchinensis) root extract lowered the bronchial thickness and infiltration of inflammatory cells, also showed a reduction in macrophages, eosinophils, IgE and Th2 cytokines in OVA-induced animals.⁴⁵ In addition, there was a significant recovery in goblet cell hyperplasia, matrix metallopeptidase-9 (MMP-9) expression and vascular endothelial growth factor (VEGF) signaling pathway upon airway remodelling in the extract-treated group. Overall, these findings provide strong evidence that A. cochinchinensis root extract prevents airway inflammation of a chronic asthma model.⁴⁵ Sim et al⁴⁶ reported that 70% ethanolic extract of Aster yomena (A. yomena) decreased Th2 type cytokines and eosinophils in the BALF and OVA-specific IgE in serum. In addition to that, A. yomena extract reduced AHR and histopathology of lungs returned to normalcy in the OVA-challenged animals.⁴⁶

The aqueous extract of Allium cepa (A. cepa) normalised the levels of nitrogen dioxide (NO₂), nitrate (NO₃), MDA, IL-4 and IgE, and the antioxidant markers such as SOD, catalase (CAT), thiol and IFN-γ as well as the IFN-γ/IL-4 ratio in OVA-sensitised animals.⁴⁷ The OVA-induced animals when treated with Artemisia argyi (A. argyi), it has reduced inflammatory cells, cytokines and AHR in asthmatic animals.⁴⁸ Furthermore, A. argyi decreased extracellular receptor kinase (ERK) phosphorylation as well as the expression of MMP-9 in asthmatic animal models, indicating its potential against allergic asthma. The aqueous and ethanolic extracts of rhizomes of Zingiber officinale (Z. officinale) treated animals showed a reduction of total WBC, eosinophils and neutrophils in BALF.⁴⁹ Moreover, Z. officinale extracts significantly inhibited Th2-mediated immune response, as evidenced by a decrease in mRNA expression levels of IL-4 and IL-5. Furthermore, there was a significant reduction in protein levels of IL-4 and IL-5 in BALF, as well as total serum IgE level by both extracts.

Seo et al⁵⁰ reported that the 80% ethanolic extract of Erythronium japonicum (E. japonicum) treatment suppressed the number of WBC and decreased the IgE level in the BALF in mice treated with OVA. Furthermore, treatment with E. japonicum extract modulated the expression of both Th2 and Th1 cell-related factor. Trigonella foenum-graecum (T. foenum-graecum) treatment decreased Th2 cytokines and increased Th1 cytokines in BALF and lung homogenates.⁵¹ Furthermore, T. foenum-graecum significantly inhibited serum IgE and anti-OVA IgG1, indicated that it is a useful agent against allergic asthma.⁵¹ Treatment of 75% hydroethanolic extract of Echinodorus scaber (E. scaber) leaves reduced total eosinophil, neutrophil, leukocyte and mononuclear cell counts in OVA-induced allergic asthma.⁵² Further, E. scaber extract ameliorated the increased in Th2 cytokines and IgE levels, which confirmed the utility of the leaves in treating allergic inflammation.

Treatment of Siphonochilus aethiopicus (S. aethiopicus) to OVA-induced mice reduced allergic lung inflammation and eosinophils percentage in BALF, although it did not influence airway hyper-reactivity.⁵³ Yu et al⁵⁴ investigated the protective effects of total flavonoids from 70% ethanolic extract of Selaginella uncinata (S. uncinata) on airway hyper-responsiveness, cytokine release and bitter taste receptors (T2Rs) signalling, emphasising on inflammatory responses in OVA-induced asthma in rats.

Treatment with S. uncinata extract attenuated AHR and goblet cell hyperplasia. Additionally, serum levels of Th2-related cytokines include IL-4, IL-5 and IL-13, total and OVA-specific IgE were reduced and IFN-γ was improved in S. uncinata-treated rats. They have also reported that S. uncinata utilises its anti-inflammatory role via T2R10/IP3R1/NFAT1 dependent signaling pathway.⁵⁴ Rosa multiflora (R. multiflora) extract inhibited eosinophil accumulation in nasal lavage fluid (NALF), the goblet cells and nasal mucosa in the nasal epithelium and mast cells in the respiratory region of the nasal cavity.⁵⁵ Furthermore, R. multiflora extract suppressed Th2-related cytokines in NALF, splenocytes and nasal-associated lymphoid tissue (NALT), whereas Th1-associated cytokine IL-12 was up-regulated, indicating that R. multiflora has therapeutic potential in treating allergic rhinitis by moderating the associations between Th1/Th2 responses.

Dussossoy et al⁵⁶ found that Morinda citrifolia (M. citrifolia) fruit juice reduced the inflammation in OVA-sensitised animals with regards to the decreased number of inflammatory cells in lung lymphocytes, macrophages, neutrophils and eosinophils. In a study, n-hexane fraction of 70% Scutellaria baicalensis (S. baicalensis) ethanolic extract has significantly suppressed the production of Th2-mediated cytokines and increased Th1-mediated cytokines against OVA-induced animals.⁵⁷ The 70% aqueous ethanolic extract of Sceptridium ternatum (S. ternatum) treatment significantly reduced AHR, raised the ratio of Th1/Th2 and reduced Cyslt1 mRNA level in a dose-dependent manner.⁵⁸ Moreover, high-dose of S. ternatum had similar efficacy as the investigated standard drug (Montelukast) in a mouse asthma model and therefore is a good potential anti-asthmatic agent.

The hydro-ethanolic extract of Curcuma longa (C. longa) significantly decreased tracheal responsiveness as well as pathological lung features in OVA-sensitised rats. Additionally, the extract decreased tracheal responsiveness to methacholine. Moreover, C. longa significantly decreased interstitial fibrosis compared to OVA-sensitized group. The C. longa treated animals showed similar or even more than that conferred by standard dexamethasone at 250 µg/kg.⁵⁹ The administration of Zanthoxylum bungeanum (Z. bungeanum) seed oil lessened airway remodelling and lung tissue injury and inhibited the infiltration of eosinophils and leukocytes into the airway by decreasing the expression levels of inflammatory chemokines and cytokines compared with OVA-treated animals.⁶⁰ Moreover, Z. bungeanum seed oil also reduced the levels of inflammatory adhesion molecules and chemokine via downregulation of extracellular signal-regulated kinase and activation of c-JUN N-terminal kinase (JNK).

Soshiho-tang, also known as “Xiao-Chai-Hu-Tang” (Chinese) and “Sho-Saiko-to” (Japanese), is composed of seven herbs (Table 1).⁶¹ The administration of Soshiho-tang water extract suppressed eosinophil influx into BALF while decreasing the levels of Th2-type cytokines.⁶² Moreover, Soshiho-tang water extract exhibited a marked decrease in mucus hypersecretion, IgE levels while significantly induced the expression of HO-1 protein. Therefore, it was determined that Soshiho-tang water extract might be another useful armamentarium against allergic asthma. In one another study, the pentaherbs formula (PHF) comprised of five traditional Chinese herbal medicines (Table 1). The water extract of PHF showed significant suppression of pulmonary eosinophilia and asthma-related cytokines IL-4 and IL-33 in BALF T.⁶³

Overall Potential Mechanism of Action of TMPs Against OVA-Induced Asthma

Due to the ethical and moral issues subjecting asthma patients to traditional herbal medicines which may exacerbate their conditions in clinical trials, the development of preclinical animal model is of great importance. OVA-induced asthma is one of the most studied allergic asthma model across the world. In this review, it was noteworthy to state that there are several variations of the model in which OVA-sensitization and OVA-challenge have been conducted via different delivery modes including repeated intraperitoneal, subcutaneous and intranasal or intratracheal administrations. The overview of the detailed protocol followed to investigate the effect of TMPs against OVA-induced asthma has been summarized in Figure 2 and Table 2. When allergen/OVA enter the lungs, antigen-presenting cells (dendritic cells) captures and present the processed antigen to the CD4⁺ T cells. Activated T cells produce copious amounts of Th2-biased cytokines (IL-4, IL5, and IL-13), which further activates the Th2 cells and B cells. Sequentially activated B cells secrete IgE, which is a stimulating factor for mast cells to produce inflammatory mediators. Furthermore, T cell activates the other innate immune cells, including eosinophils which aggravate the inflammatory situation. TMPs which composed of heterogenous components inhibit the allergen/OVA-induced asthma by inhibiting either the antigen presentation, cytokine secretion or the release of inflammatory mediators. The detailed mechanism of TMPs against OVA-induced asthma was shown in Figure 3.

Table 2 Study Protocol and the Protective Mechanism of TMPs Against OVA-Induced Asthma

Figure 2 Protocol followed to investigate TMPs against OVA-induced asthma. OVA-induced animal asthma model: (A) mice, (B) Guinea pig, (C) Rat. The above figure depicts the timeline of OVA sensitization and challenge followed by the end readouts. Schedules of sensitization and challenge depend on the type of animal model and routes of administration. In addition, varying OVA doses (with or without adjuvant) have been used both in sensitization and challenge (for more information, see Table 1).

Figure 3 Possible mechanism of action of TMPs against OVA-induced asthma. As an allergen, OVA-induces airway inflammation and hyperresponsiveness. As a protein OVA recognized, processed and presented by the antigen-presenting cells. Upon presentation, CD4+ T helper (Th0) cells are activated and polarized toward Th2 phenotype, which activates eosinophils (Eosinophilic asthma), mast cells, and basophils to secret inflammatory mediators. OVA directly or indirectly (via Th cells mediated) activates the B lymphocytes to secret IgE, which is the main correlative factor in allergen-induced asthma. TMPs may either act by inhibiting antigen presentation or cytokine secretion or other inflammatory mediators (histamine, leukotrienes, and others). The figure was created with the support of https://biorender.com under the paid subscription.

Challenges and Opportunities of TMPs for the Treatment of Asthma

Since asthma is a chronic disease, conventional management for asthma generally requires institution of extensive bronchodilators and corticosteroids treatment. Nevertheless, drugs, especially steroids, are allied with various side effects and refractory responses. Therefore, TMPs may provide a better alternative strategy against asthma. Nevertheless, scientific validation remains lacking and is urgently required to confirm their utility either as a complementary alternative therapy or as an adjunct to conventional therapies.⁶⁴

Based on the established literatures, administration of the reported medicinal plant extracts to OVA-induced animals can effectively inhibit the entry of inflammatory cells into the lungs, where a significant reduction in the total eosinophil and leucocyte populations in the lung tissue can be seen. All the medicinal plants stated in this review are used to treat respiratory inflammation, asthma or its related diseases for many years based on the traditional Indian medicine (Ayurveda), traditional Chinese medicine and other indigenous medicinal systems. The scientific reports reviewed have demonstrated that all these medicinal plants have potential anti-asthmatic effect against OVA-induced asthma model, which is similar to asthma experienced by humans which strongly support their traditional uses. However, further studies are required since most are established in the earlier phases of study and clinical trials are encouraged. Additionally, the safety, toxicity and side effect data associated with TMPs are severely lacking and have to be addressed. TMPs have several chemical constituents which are responsible for the management of asthma or its relevant complications. Thus, the exact active constituent responsible for its anti-asthmatic effects should be evaluated. Furthermore, its pharmacokinetic, pharmacological and clinical data has to be investigated to confirm its potential as a lead compound against asthma.

Moreover, an archive of information on herbal medicine from various cultural backgrounds (Indian, Chinese, Japanese, Korean, African and Arabian) for the management and treatment of asthma.^65–81 To date, knowledge on the medicinal plants used for asthma medication and their mode of preparations are limited to some herbal medicine practitioners although some clinical and pharmacological evidences are available.⁶⁸ Therefore, there is insufficient evidence to make recommendations to use of these TMPs in clinical practice since the global acceptance and utilisation of herbal medicines is dependent on their safety and efficacy.

Our review suggests that OVA-induced animal model may be used to confirm the effectiveness of the TMPs. The model confirms the effectiveness of herbal medicines on typical inflammatory processes as seen in asthma inflammation which confirms the clinical biological plausibility of herbal medicines effects. Several new animal models are currently available for preclinical screening to confirm the efficacy of the anti-asthmatic drugs. Thakur et al⁸² developed a new model to confirm the anti-asthmatic effects in which the combination of OVA with LPS demonstrated the phenotypes of severe lymphocytic inflammation, neutrophilic, eosinophilic and bronchoconstriction, when compared to a single allergen. Few other studies have also shown that pulmonary neutrophilia in mouse is triggered by the combination of LPS with commercial OVA.^83,84 These new models can be exploited to evaluate the severe anti-asthmatic effect of TMPs.

Very recently, several clinical studies have reported the use of TMPs for asthma treatment. Dulla and Jahan⁷⁰ indicated that some traditional Chinese medicines indicated their effectiveness against asthma in children when compared to modern medicines such as salbutamol and montelukast. In another research, some of the traditional herbal medicines in East-Asia were used as adjuncts in improving acute and chronic asthma outcomes⁸⁵ which boosts the evaluation of TMPs for clinical trials. Wang et al⁸⁶ reported that the clinical efficacy of traditional Chinese medicine, which binds to proteins, are potential targets for asthma therapy. Another approach is a combination therapy, when herbal medicines used together with modern medicines enhance asthma outcomes as compared to the use of pharmacotherapies alone.⁸⁷ Zhou et al⁸⁸ indicated that acupuncture ameliorates asthmatic pulmonary function associated to metallothionein-2. Based on all the above studies, it is hypothesised that the combination of acupuncture with TMPs treatments also provide better therapeutic outcomes. Future research on asthma treatment should be focused in this direction and more advanced studies are required to confirm the use of TMPs in combination with conventional therapies.

Conclusion and Future Perspectives

In this review, we highlighted 27 traditional medicinal plant species and two polyherbal extracts that have been investigated for their anti-asthmatic potential using OVA-induced models. Our review revealed that most of the investigated medicinal plants and their extracts promote attenuation of asthma symptoms in experimental animals and supports its traditional information. Nevertheless, the toxicological profiles of the plant extracts remain unreported since most of the studies focused only on their anti-asthmatic potentials. Additionally, there is a severe lack of information on the efficacy, safety and the required dosage to induce the in vivo anti-asthma activity which should be the focus in future studies. The lack of scientific reports and limited information on the isolated compounds responsible for anti-asthmatic actions is another negative factor that should be addressed in future studies. In conclusion, the vast potentials of the TMPs should be explored for the development of new drugs to enhance existing anti-asthmatic treatment as an adjuvant or to be used as a new armamentarium against asthma.