**6. Chinese single herbs use in children with asthma**

We described several single herbs frequently used for asthmatic children in Taiwan (shown in Table 2), including Zhe Bei Mu (*Fritillaria thunbergii*), Xing Ren (*Semen Armeniacae Amarum*), Huang Qi (*Astragalus membranaceus*), Qian Hu (*Peucedanum praeruptorum Dunn*), Gan Cao (*Glycyrrhiza uralensis*), Sang Bai Pi (*Cortex mori radicis*), Ban Xia (*Pinellia ternate*), Bo He (*Mentha haplocalyx*), Da Huang (*Rheum palmatum*), Jie Geng (*Platycodon grandiflorum*), Huang Qin (*Scutellaria baicalensis*), and Yu Xing Cao (*Houttuynia cordata Thunb.*).

#### **6.1. Zhe Bei Mu**

Zhe Bei Mu is used as an antitussive therapy and expectorant in TCM. Its extract inhibited histamine release from rat peritoneal mast cells in a concentration-dependent manner. Moreover, it also inhibits the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) in human mast cell line-1 (HMC-1) cells and components of the mitogen-activated protein kinase (MAPK) pathway in mast cells [43].

#### **6.2. Xing Ren**

Studies on the OVA-sensitized allergic airway inflammation model in mice revealed that XQLT significantly inhibited the antigen-induced immediate asthmatic response and late asthmatic response in actively sensitized mice. XQLT was shown to reduce the production of Th2-associated cytokines, IL-4 and IL-5, and to restore the production of the Th1 cellassociated cytokine, IFN-γ [39]. Anti-OVA IgE antibody levels were reduced in the BALF of sensitized mice after oral administration of XQLT [39]. Furthermore, XQLT was shown to have an anti-asthmatic effect, which is partly mediated by stimulation of beta-2-adrenocep‐ tors, leading to bronchorelaxation; furthermore, XQLT inhibits the infiltration of eosino‐

Ding-Chuan-Tang (DCT), another TCM, has been used in the treatment of bronchial asthma for several centuries. DCT is composed of nine herbs, including Ma Huang (*Herba Ephedrae*), Gan Cao (*Radix Glycyrrhizae*), Ban Xia (*Rhizoma Pinelliae*), Bai Guo (*Semen Ginkgo*), Kuan Dong Hua (*Flos Farfarae*), Sang Bai Pi (*Cortex Mori*), Su Zi (*Fructus Perillae*), Xing Ren (*Semen Arme‐ niacae Amarum*), and Huang Qin (*Radix Scutellariae*). According to TCM principles, this decoction is frequently prescribed for children with coughing, wheezing, and chest tightness. One study of a murine OVA-sensitized allergic airway inflammation model revealed that DCT significantly inhibited the increase of eosinophils in the airway and caused concentrationdependent bronchorelaxation via a beta-2 adrenergic effect [41]. A randomized, double-blind clinical trial [42] conducted to assess the add-on effect of DCT showed that AHR significantly improved after weeks of DCT treatment compared with that after placebo use. In addition, patients in the DCT group also showed superior clinical improvement and used less medica‐ tion than in the placebo group. This study suggested that addition of DCT to conventional treatment could further improve AHR, even in patients with well-controlled asthma. How‐ ever, this study did not find a significant reduction in IgE levels and FEV<sup>1</sup> with DCT treatment,

We described several single herbs frequently used for asthmatic children in Taiwan (shown in Table 2), including Zhe Bei Mu (*Fritillaria thunbergii*), Xing Ren (*Semen Armeniacae Amarum*), Huang Qi (*Astragalus membranaceus*), Qian Hu (*Peucedanum praeruptorum Dunn*), Gan Cao (*Glycyrrhiza uralensis*), Sang Bai Pi (*Cortex mori radicis*), Ban Xia (*Pinellia ternate*), Bo He (*Mentha haplocalyx*), Da Huang (*Rheum palmatum*), Jie Geng (*Platycodon grandiflorum*), Huang Qin

Zhe Bei Mu is used as an antitussive therapy and expectorant in TCM. Its extract inhibited histamine release from rat peritoneal mast cells in a concentration-dependent manner. Moreover, it also inhibits the production of inflammatory cytokines (IL-6, IL-8, and TNF-α) in

phils into the airway [40].

228 Asthma - From Childhood Asthma to ACOS Phenotypes

as compared to placebo [42].

**6.1. Zhe Bei Mu**

**6. Chinese single herbs use in children with asthma**

(*Scutellaria baicalensis*), and Yu Xing Cao (*Houttuynia cordata Thunb.*).

**5.6. Ding-Chuan-Tang**

Xing Ren has long been used in TCM to control acute lower respiratory tract infection and asthma as a result of its expectorant and anti-asthmatic activities. Xing Ren was shown to have anti-asthmatic activity and selectively inhibit the Th2 response in a mouse model by decreasing eosinophils and IL-4 in the airway [44].

#### **6.3. Huang Qi**

Huang Qi has a long history of medicinal use for asthma treatment in China. It increases metabolism and stimulates tissue regeneration, and it is used to treat colds, allergies, digestive problems, and fatigue in TCM. Huang Qi was shown to inhibit the Th2 response. It significantly reduced AHR, eosinophil counts, and IL-4, IL-5, and IL-13 levels and increased INF-γ levels in BALF. Histological studies showed that Huang Qi markedly decreased inflammatory infiltration, mucus secretion, and collagen deposition in lung tissues. CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a significant role in the regulation of asthma, and the induction of allergen-specific Tregs has become one appealing strategy for asthma therapy [45–47]. Huang Qi was shown to increase the population of CD4+ CD25+ Foxp3+ Tregs and promote *Foxp3* mRNA expression in a rat model of asthma [47]. This suggests that the anti-asthmatic effects of Huang Qi are at least partially associated with CD4+ CD25+ Foxp3+ Tregs.

#### **6.4. Qian Hu**

Qian Hu is a TCM commonly used for the treatment of asthma. Its major constituents, coumarins, were presumed to be responsible for its efficacy. Qian Hu was shown to reduce AHR and airway eosinophilic inflammation significantly, improve pathologic lesions of the lungs, reduce levels of IL-4, IL-5, and IL-13 in BALF and OVA-specific IgE in serum, inhibit the expression of TGF-β1 in lungs, and upregulate levels of IL-10 and IFN-γ in BALF, as well as the percentage of CD4+ CD25+ Foxp3+ regulatory T cells in the spleen [48, 49]. This suggests that Qian Hu has great therapeutic potential for the treatment of allergic asthma.

#### **6.5. Gan Cao**

Gan Cao, commonly called "licorice," is one of the most commonly used herbs in TCM. Airway eosinophilic inflammation is a major feature of allergic asthma. Eotaxin-1 is involved in the recruitment of eosinophils to sites of antigen-induced inflammation in asthmatic airways. Licorice flavonoids can inhibit eotaxin-1 secretion by human fetal lung fibroblasts in vitro [50]. Licorice flavonoids also significantly reduced eosinophilic pulmonary inflammation, serum IgE, IL-4, and IL-13 levels but also increased IFN-γ production in lung cell cultures in response to antigen stimulation [51]. Glycyrrhizic acid is the main bioactive ingredient of licorice and has been shown to exert anti-asthmatic effects by modulating Th1/Th2 cytokines (IL-4, IL-5, IL-13 inhibition, IFN-γ increase in BALF) and enhancing CD4+ CD25+ Foxp3+ Tregs in OVA- sensitized mice [52]. Histological studies demonstrated that glycyrrhizic acid substantially inhibited OVA-induced eosinophilia in lung and airway tissues [52].

#### **6.6. Sang Bai Pi**

Sang Bai Pi (*Cortex mori radicis*), the root epidermis of *Morus alba* L., has been traditionally used for cough treatment in TCM. In OVA-induced asthma model mice [53], Sang Bai Pi significantly reduced AHR, inhibited the production of histamine and IgE in serum, and decreased airway eosinophil infiltration in BALF and lung tissue. Sang Bai Pi significantly attenuated the secretion and mRNA levels of Th2 cytokines, such as IL-4, IL-5, and IL-13. In addition, Sang Bai Pi significantly increased mRNA expression of IFN-γ, a Th1 cytokine. Furthermore, Sang Bai Pi can exert anti-asthmatic effects by enhancing CD4+ CD25+ Foxp3+ Tregs.

#### **6.7. Ban Xia**

Ban Xia is a commonly used Chinese herb, with high bioactivity against cough and vomiting, and eliminating the stagnation of phlegm. Ban Xia significantly attenuated OVA-induced influx of the total number of leukocytes, eosinophils, neutrophils, macrophages, and lympho‐ cytes into the lungs, decreased airway mucus production, and attenuated levels of IL-4, IL-5, IL-13, and TNF-α, in a dose-dependent manner. Ban Xia also significantly reduced the plasma levels of histamine, total IgE and OVA-specific IgE [54, 55].

#### **6.8. Bo He**

Bo He has been reported to have pharmacological effects, including the lowering of body temperature and relaxation of the muscles of the digestive tract. The herb is traditionally used for the treatment of high fever, mild chills, cough, thirst, and sore throat and to combat nausea, vomiting, and flatulence. Bo He significantly inhibited eosinophils, neutrophils, lymphocytes, macrophages, and total cells in BALF of OVA-challenged mice. Bo He also decreased specific IgE and Th2 cytokines, such as IL-4 and IL-5, in BALF and lung tissue. Airway inflammation and hyperreactivity in asthma are likely to involve oxidative stress to the lung, and excess production of reactive oxygen species (ROS) by immune cells may play an important role in airway injury. An increase in the generation of ROS in the airway and BALF has been noted in OVA-induced asthma models. Bo He has been shown to reduce the ROS in the BALF of asthmatic model mice, as did montelukast, which has been used widely as an anti-asthmatic drug [56].

#### **6.9. Da Huang**

Da Huang is used to cure stomach illness and as a "cathartic" to relieve severe constipation as well as a poultice for fevers and edema caused by inflammation. Emodin, one of the major compounds of Da Huang, displays a number of biological activities, such as anti-microbial, immunosuppressive, anti-inflammatory, anti-tumor, and anti-atherosclerotic activities. Moreover, emodin attenuates mast cell-dependent passive anaphylactic reactions in IgEsensitized mice. Emodin has also been shown to reduce IgE and Th2 cytokine levels in OVA- induced asthma mice. The inhibition of AHR by emodin may be associated with the reduction of IL-4, IL-5, and IL-13 production and eosinophilia aggregation into the lungs [57].

#### **6.10. Jie Geng**

sensitized mice [52]. Histological studies demonstrated that glycyrrhizic acid substantially

Sang Bai Pi (*Cortex mori radicis*), the root epidermis of *Morus alba* L., has been traditionally used for cough treatment in TCM. In OVA-induced asthma model mice [53], Sang Bai Pi significantly reduced AHR, inhibited the production of histamine and IgE in serum, and decreased airway eosinophil infiltration in BALF and lung tissue. Sang Bai Pi significantly attenuated the secretion and mRNA levels of Th2 cytokines, such as IL-4, IL-5, and IL-13. In addition, Sang Bai Pi significantly increased mRNA expression of IFN-γ, a Th1 cytokine. Furthermore, Sang

Ban Xia is a commonly used Chinese herb, with high bioactivity against cough and vomiting, and eliminating the stagnation of phlegm. Ban Xia significantly attenuated OVA-induced influx of the total number of leukocytes, eosinophils, neutrophils, macrophages, and lympho‐ cytes into the lungs, decreased airway mucus production, and attenuated levels of IL-4, IL-5, IL-13, and TNF-α, in a dose-dependent manner. Ban Xia also significantly reduced the plasma

Bo He has been reported to have pharmacological effects, including the lowering of body temperature and relaxation of the muscles of the digestive tract. The herb is traditionally used for the treatment of high fever, mild chills, cough, thirst, and sore throat and to combat nausea, vomiting, and flatulence. Bo He significantly inhibited eosinophils, neutrophils, lymphocytes, macrophages, and total cells in BALF of OVA-challenged mice. Bo He also decreased specific IgE and Th2 cytokines, such as IL-4 and IL-5, in BALF and lung tissue. Airway inflammation and hyperreactivity in asthma are likely to involve oxidative stress to the lung, and excess production of reactive oxygen species (ROS) by immune cells may play an important role in airway injury. An increase in the generation of ROS in the airway and BALF has been noted in OVA-induced asthma models. Bo He has been shown to reduce the ROS in the BALF of asthmatic model mice, as did montelukast, which has been used widely as an anti-asthmatic

Da Huang is used to cure stomach illness and as a "cathartic" to relieve severe constipation as well as a poultice for fevers and edema caused by inflammation. Emodin, one of the major compounds of Da Huang, displays a number of biological activities, such as anti-microbial, immunosuppressive, anti-inflammatory, anti-tumor, and anti-atherosclerotic activities. Moreover, emodin attenuates mast cell-dependent passive anaphylactic reactions in IgEsensitized mice. Emodin has also been shown to reduce IgE and Th2 cytokine levels in OVA-

CD25+

Foxp3+

Tregs.

inhibited OVA-induced eosinophilia in lung and airway tissues [52].

Bai Pi can exert anti-asthmatic effects by enhancing CD4+

levels of histamine, total IgE and OVA-specific IgE [54, 55].

**6.6. Sang Bai Pi**

230 Asthma - From Childhood Asthma to ACOS Phenotypes

**6.7. Ban Xia**

**6.8. Bo He**

drug [56].

**6.9. Da Huang**

Jie Geng is commonly used as a cough suppressant and expectorant for treatment of common colds, cough, sore throat, tonsillitis, and chest congestion. An aqueous extract of Jie Geng inhibited OVA-specific IgE levels in BALF. Inflammatory cell infiltration and mucus hyper‐ secretion were also inhibited by Jie Geng extracts. Furthermore, Jie Geng extracts decreased the generation of ROS in BALF, as well as NF-κB nuclear translocation in OVA-induced asthma mouse model [58]. Jie Geng is abundant in saponins, which inhibit IgE antibody-induced increases in IL-4 and TNF-α expression in RBL-2H3 cells. Saponins suppressed dinitrophenyl (DNP)–IgE antibody–induced phosphorylation of Syk, and further downstream, Changkil saponins (CKS) also inhibited the phosphorylation of Akt and MAPKs [59].

#### **6.11. Huang Qin**

Huang Qin is one of the most widely used medicinal herbs for the treatment of inflammation. Ethanol extracts of Huang Qin may effectively suppress inflammation by downregulating the expression of various inflammatory mediators (such as histamine) and reducing the produc‐ tion of inflammatory cytokines (such as IL-8 and TNF-α) as well as MAPK activation [60]. Skullcapflavone II is a flavonoid derived from Huang Qin (*Scutellaria baicalensis*). Skullcapfla‐ vone II significantly reduced AHR, airway eosinophilia, Th2 cytokine production, and TGFβ1 levels in BALF and lungs in an OVA-induced asthma mouse model [61].

#### **6.12. Yu Xing Cao**

Yu Xing Cao is also used in folk medicine for diuresis and detoxification and for its anti-viral, anti-bacterial, and anti-leukemic activities. It has been used for the treatment of cough, pneumonia, bronchitis, uteritis, eczema, herpes simplex, acne, and chronic sinusitis. Ethanol extracts of Yu Xing Cao downregulate the expression of IL-4, IL-5, thymus and activationregulated chemokine (TARC), and CCR4 receptor but do not have the same effect on IFN-γ [62].




**Herbal name (Latin name)**

232 Asthma - From Childhood Asthma to ACOS Phenotypes

**Xing Ren** (*Semen Armeniacae Amarum*)

**Huang Qi** (*Astragalus membranaceus*)

**Qian Hu** (*Peucedanum praeruptorum Dunn*)

**Gan Cao** (*Glycyrrhiza*

**Sang Bai Pi** (*Cortex mori*

*uralensis*)

*radicis*)

**Pictures Possible mechanisms**

AHR [44]

Decreases Th2 response; reduces IL-4 levels, eosinophilic inflammation, and

Decreases Th2 response; increases IFN-γ level; decreases IL-4, IL-5, IL-13, and TGF-β1 levels; reduces eosinophilic and neutrophilic inflammation; reduces AHR, collagen deposition, and mucus

Decreases Th2 response; increases IFN-γ and IL-10 levels; decreases IL-4, IL-5, IL-13, specific IgE, and TGF-β1 levels;

Decreases Th2 response; increases IFNγ; decreases IL-4, IL-5, IL-13, specific IgE, and eotaxin-1 levels; reduces eosinophilic inflammation; increases

Decreases Th2 response; decreases IL-4, IL-5, IL-13, and specific IgE levels; reduces AHR, eosinophilic

inflammation, and histamine release;

CD25+

FoxP3+

regulatory T

CD25+

regulatory T cells [48,

regulatory T cells [50–

FoxP3+

secretion; increases CD4+

regulatory T cells [45–47]

reduces AHR, eosinophilic inflammation; increases

FoxP3+

FoxP3+

CD4+ CD25+

CD4+ CD25+

increases CD4+

cells [53]

52]

49]

**Table 2.** Single herbs frequently used for asthmatic children

### **7. Acupuncture use in children with asthma**

Acupuncture is a TCM therapeutic approach involving the stimulation of points on the body by using needles. For thousands of years, acupuncture has been used to treat several conditions, including asthma. Other methods of stimulation are traditionally used, such as electroacupuncture, laser acupuncture, and transcutaneous electrical nerve stimulation. There is evidence that acupuncture can reduce eosinophils in peripheral blood and decrease secretory IgA (sIgA) and total IgA levels in the saliva and nasal secretions of patients with allergic asthma [63]. The role of eosinophil activation in asthma has been well documented. sIgA is a potent stimulus for eosinophils and represents the main trigger for eosinophil degranulation. After acupuncture treatment, the reduction of sIgA levels and the decrease in the numbers of eosinophils may be associated with the amelioration of eosinophilic inflam‐ mation in patients with allergic asthma [63]. The numbers of CD3+ , CD4+ , and CD8+ T lymphocytes in the peripheral blood were significantly increased, without significant cortisol changes, in patients with allergic asthma treated by acupuncture [63]. It has been shown that electroacupuncture is prominent in promotion of CD4+ CD25+ FoxP3+ Tregs in an OVAinduced experimental model [64]. Furthermore, acupuncture has also been shown to inhibit AHR, eosinophils, neutrophils, specific IgE, Th1 cytokines, and the NF-κB pathway in OVAinduced experimental asthma [65].

#### **8. Acupuncture point application**

Acupuncture point application therapies, combining Chinese herbal medicine and acupunc‐ ture points, have been extensively applied for the treatment of allergic rhinitis (AR) and asthma [66]. Summer acupuncture point application treatment, also known as San-Fu-Tie or San-Fu-Jiu, is one type of direct moxibustion administered in the summer through the direct applica‐ tion of an irritating herbal paste to acupuncture points. The basic herbal prescription of San-Fu-Tie is usually composed of Bai Jie Zi (*Semen Sinapis Albae*), Xi Xin (*Herba Asari*), Gan Sui (*Radix Kansui*), and Yan Hu Suo (*Rhizoma Corydalis*) [66, 67]. These herbs are ground into a powder, mixed, and made into paste using stale ginger juice. The standard acupoints include Fei-shu (BL-13) and Feng-men (BL-12), the meridians named Taiyang Bladder Meridian of Foot [67]. Numerous studies have shown significant efficacy through acupoint stimulation in treatment of asthma, such as improvement of lung function, a decrease in cytokines (IL-4, IL-6, IL-8, and IL-10), and restoring the Th1/Th2 balance toward Th1 [66, 67]. Few adverse effects have been reported, except for mild skin allergy, or local swelling and blisters.
