Bacterial and viral infections account for up to 70% of all pathogenic diseases in humans (Smith et al., 2014). Influenza is one of the most prevalent respiratory diseases, and accounts for nearly 5–15% of people all respiratory infections. Although most patients recover, about 0.5 million people die of influenza each year (Petrova and Russell, 2018). The outbreak of COVID-19 has become a global health emergency on a pandemic scale, which has given rise to various studies and developments of antiviral drugs and vaccines. Coronaviruses identify the angiotensin-converting enzyme 2 (ACE2) as the main entry point into the respiratory epithelial cells of the host (Zhou et al., 2020a). Potential targets, including retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5/mitochondrial antiviral signaling/TNF receptor-associated factor 3/interferon regulatory factor 3 (IRF3)/IRF7, and Toll-like receptors (TLRs)/TIR-domain-containing adapter-inducing interferon-β/nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (MAPK)/activating protein-1 (AP-1) pathways as intercellular sensors have been detected to study translation and budding process of SARS-CoV-1 and MERS viruses infection with SARS-CoV-1 using in vitro and in vivo models (Stertz et al., 2007), which may cause cellular death, hyperinflammation, and cytokine storm during viral infections (Azkur et al., 2020).

TCM could be a great potential resource for the development of innovative pharmacotherapies against infections. It has been reported that Lianhuaqingwen granules (active ingredients including Forsythia suspensa (Thunb.) Vahl, Lonicera japonica Thunb., and Prunus mandshurica (Maxim.) Koehne., Rosaceae) (Jia et al., 2015), Shufeng Jiedu capsule (active ingredients including Forsythia suspensa (Thunb.) Vahl, Strobilanthes cusia (Nees) Kuntze, and Bupleurum chinense DC.) (Liu et al., 2019a), Huoxiang Zhengqi dropping pills (active ingredients including Pogostemon cablin (Blanco) Benth., Platycodon grandiflorus (Jacq.) A.DC., and Pinellia ternata (Thunb.) Makino) (Li et al., 2006) and Haishiyi formula (active ingredients including Ephedra sinica Stapf, Prunus mandshurica (Maxim.) Koehne., and Atractylodes macrocephala Koidz.) can improve clinical symptoms, such as fatigue, cough, and fever, reduce the usage rate of antibiotics, and prevent the progression to severe COVID-19 (Xiao et al., 2020a; Tian et al., 2020; Xia et al., 2021). Currently, canti-COVID-19 agents mainly target SARS-CoV-2 spike receptor-binding domain or ACE2 enzyme activity to block the entry of COVID-19 to the cells. EGCG from Eriobotrya japonica (Thunb.) Lindl., and Ginkgo biloba L., and isorhamnetin found in Lepidium apetalum Willd., Eriobotrya japonica (Thunb.) Lindl., Ginkgo biloba L., and Aster tataricus L.f. exhibit the ability to prevent SARS-CoV-2 from entering into ACE2⁺ cells (Henss et al., 2021; Maiti and Banerjee, 2021; Zhan et al., 2021). Neochlorogenic acid from Tussilago farfara L. and Lianhuaqingwen granules inhibit the ACE2 enzyme activity (Chen et al., 2021a). Hesperidin and hyperoside from Eriobotrya japonica (Thunb.) Lindl. show antiviral and anti-inflammatory effects against H1N1 virus (Ding et al., 2018; Ling et al., 2020). In H9N2 virus-induced pneumonia, kaempferol inhibits TLR4/Myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathways to reduce the production of inflammatory factors and enhance antioxidant ability (Zhang et al., 2017a). β-sitosterol from eight herbs, such as Morus alba L., and Datura metel L., inhibits RIG-I and signal transducer and activator of transcription 1 (STAT1) signaling pathway to improve interferon sensitization (Zhou et al., 2020b). As for bacterial infections, it has been reported that benzaldehyde has a good inhibitory effect on a variety of bacteria (Lee et al., 2014a). SARS-CoV-2 spike receptor-binding domain, ACE2, and inflammatory response are essential targets of these bioactive compounds, which may be related to Toll-like receptor and MAPK signaling pathways. Overall, the antiviral and antibacterial effects of these active compounds mentioned above are shown in Table 1.

ALI is common in pulmonary infection, lung contusion, pulmonary embolism, and near-drowning, it can lead to acute respiratory distress syndrome (ARDS) (Suresh et al., 2000). The mortality of ARDS ranges from 35 to 46%, which is higher than mortality of breast cancer or HIV infection (Fan et al., 2018). Patients recovered from ARDS may experience physical, neuropsychiatric, and neurocognitive morbidity that persistently impair their quality of life (Fan et al., 2014). Inflammation, bacterial and viral infections are the most common causes of ALI (Fan and Fan, 2018). The pathogenesis of ALI is believed to be related to inflammation, oxidative stress, cell apoptosis, and hypoxia, involving major cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β, IL-9, and IL-8, as well as the chemokines, such as chemokine-2 (CCL-2), monocyte chemotactic factors (MIP), and macrophage chemoattractant protein (MCP). The critical signaling pathways mainly include NF-κB, MAPK, nucleotide-binding oligomerization domain, NOD-like receptor family pyrin domain containing 3 (NLRP3), TLRs, adrenergic receptors, the Janus kinase (JAK)/STAT, and AMP-activated protein kinase (AMPK)- anti-thymocyte globulin (ATG7) signaling pathways (Chang et al., 2018a; Nadeem et al., 2018). The potential targets include of superoxide dismutase (SOD), glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H, quinone-1 (NQO1), catalase (CAT), glutathione peroxidase (GSH-Px), and heme oxygenase-1 (HO-1) (Sun et al., 2018; Zhou et al., 2020a). Collectively, intrapulmonary oxidants derived from either activated lung macrophages or oxidant-generating enzymes delivered into the lung are two main pathways of oxidative stress, which can induce ALI and, more seriously, ARDS (Ward, 2010).

The model of ALI is mainly based on the induction by lipopolysaccharide (LPS) in in vivo and in vitro experiments. Other inflammatory substances and harmful chemicals such as N-methyl-d-aspartate, methamphetamine, and paraquat (PQ) are also used in ALI studies. TNF-α and other cytokines are commonly used in the in vitro model construction of ALI. The changes in pulmonary function, lung wet/dry ratios, the morphology of lung tissue, and inflammatory factors in alveolar lavage fluid and serum are generally used to evaluate the inflammatory response. Canonical NF-κB pathway directly induces proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. Subsequently, the activation of IL-1R1 and TNFR1 can make a positive feedback to activate the crucial pathway of inflammation via the NF-κB pathway (Yu et al., 2020a). Ellagic acid, apigenin, EGb761, galangin, isorhamnetin, and kaempferol from Ginkogo biloba, Aster tataricus L.f., Eriobotrya japonica (Thunb.) Lindl., and Lepidium apetalum Willd. can reduce the production of inflammatory cytokines and oxidative stress to prevent LPS-induced ALI in mice through the NF-κB pathway (Cornélio Favarin et al., 2013; Huang et al., 2013; Lee et al., 2014b; Shu et al., 2014; Wang et al., 2014; Chi et al., 2016; Li et al., 2016; Luan et al., 2016; Liu et al., 2018a; Qian et al., 2019; Júlio de Souza et al., 2020; Ren et al., 2021). TLR4/MYD88, an upstream player of the NF-κB pathway, mediates the inflammation and ALI. Both processes are ameliorated by ferulic acid and hesperidin from Aster tataricus L.f. and Eriobotrya japonica (Thunb.) Lindl., which have anti-inflammatory activities and protective effects against ALI by downregulating cytokines and chemokines (Ma et al., 2015; Wu et al., 2021). Furthermore, myeloid differentiation 2 (MD2) and high-mobility group box 1 (HMGB1) are the key targets of hesperidin, through which it can effectively inhibit inflammation during ALI (Liu et al., 2015; Ma et al., 2015). Rutin and moracin M from Eriobotrya japonica (Thunb.) Lindl. and Morus alba L. improve ALI through a crosstalk of the MAPK and the NF-kB signaling pathways (Yeh et al., 2014; Liu et al., 2015; Ma et al., 2015; Huang et al., 2016; Lee et al., 2016; Ye et al., 2019). The NLRP3 inflammasome processes the interleukin precursors into their mature forms, such as IL-1β and IL-18, which results in inflammation (Afonina et al., 2017). The bioactive components from Prunus mandshurica (Maxim.) Koehne, Eriobotrya japonica (Thunb.) Lindl., and Morus alba L. amygdalin and resveratrol suppress NF-κB activity and ROS production via inhibiting NLRP3 inflammasome (Jiang et al., 2016a; Zhang et al., 2017b). SIRT1, the NAD⁺-dependent protein deacetylase, provides “stop signals” for inflammatory and oxidative stress (Jiang et al., 2016a; de Oliveira et al., 2019; Tsai et al., 2019). Resveratrol and oleanolic acid from Perilla frutescens (L.) Britton, Eriobotrya japonica (Thunb.) Lindl. and Morus alba L. reduce PTEN and NF-κB acetylation through the activation of SIRT1 (Peng et al., 2019; Wang et al., 2020a). Quercetin and formononetin from most of the 10 herbs enhance Nrf2/HO-1-mediated cytoprotective effects and prevent LPS-induced lung inflammation (Ma et al., 2013; Takashima et al., 2014; Wang et al., 2018a; Chen et al., 2021b). Luteolin downregulates cytokine and oxidative stress, ICAM-1 through the NF-κB pathway and induces Treg differentiation against ALI (Rungsung et al., 2018; Xie et al., 2021). According to the role of miRNAs in lung inflammation, it has been shown that resveratrol downregulates miR-193a to target transforming growth factor-β2 (TGF-β2), TGFβ receptor (TGFβR3), and death receptor-6 (Alghetaa et al., 2018). Liquiritin from Prunus mandshurica (Maxim.) Koehne inhibits the expression of TRPV1 and TRPA1 thereby providing anti-inflammatory and anticough effects (Liu et al., 2020). Taken together, 16 active compounds in 10 herbs have potential roles in inhibiting lung inflammation and injury through NF-κB, MAPK, NLRP3, PI3K/Akt, SIRT1, and HO-1 pathways. More details for the therapeutic effects and molecular mechanism of these compounds against inflammation and ALI are shown in Table 2.

The pathogenesis of COPD is related to chronic inflammation, oxidative stress, cellular senescence, corticosteroid resistance, cell apoptosis, and changes in pulmonary histology and functions. The proinflammatory cytokines and chemokines (TNF-α, IL-1, IL-6, and IL-8), the signaling pathways (NF-κB and MAPK pathways), and various stress-related molecules (SOD, MDA, GSH) participate in the different pathological stages of COPD (Yang et al., 2020). IL-8 recruits neutrophils and secretes several neutrophil elastases and metalloproteases, e.g., MMP-9, which results in alveolar destruction. GM-CSF and IL-6 contribute to the increase in airway smooth muscle mass and proliferation, leading to bronchial obstruction (Knobloch et al., 2018; Jamal Jameel et al., 2021). Human airway smooth muscle cells (HASMCs) contributing to the secretion of cytokines and chemokines are related to non-type 2 airway inflammation and remodeling processes in COPD (Knobloch et al., 2013; Knobloch et al., 2016; Knobloch et al., 2019). Exposure to gases from cigarette smoking and inhaled particles such as PM2.5 are two archetypical inducing factors of COPD, which means that cigarette smoke and PM2.5 are commonly used for establishing in vivo and in vitro models of COPD (Rabe and Watz, 2017). Many studies have shown that multiple herbs, such as Tussilago farfara L., Eriobotrya japonica (Thunb.) Lindl., and Morus alba L. can inhibit the progression of COPD. Tussilagone and EGCG from the herbs mentioned above enhance the antiproliferative activity through the inhibition of the NF-κB pathway (Choi et al., 2018; Lakshmi et al., 2020). Amygdalin ameliorates the process of epithelial-mesenchymal transition (EMT) through the TGF-β/Smad pathway in cigarette smoke-exposed BEAS-2B cell line and mice model (Wang et al., 2019). Ursolic acid attenuates emphysema and enhances airway remodeling via unfolded protein response (UPR) signaling pathways (Lin et al., 2019; Li et al., 2020b). Liquiritin can reduce pulmonary inflammation by targeting the TGF-β pathway (Guan et al., 2012). Resveratrol inhibits the autophagic process and decreases IL-1β production by inactivation of NLRP3 inflammasome (Ding et al., 2019) or regulation of p53 destabilization (Navarro et al., 2017). Alveolar macrophages are important immune and inflammatory regulatory cells in the lung tissue (Gerlach et al., 2015). Resveratrol reduces the expression of MMP-9, GM-CSF and inflammatory mediators including IL-6, IL-8, and MCP-1 in alveolar macrophages under the stimulation of different harmful substances (Culpitt et al., 2003; Knobloch et al., 2011). Other reports have shown that resveratrol inhibits cytokines and chemokines (CCL-2, IL-6, IL-8) and ameliorates bronchial obstruction-related secretory proteins (GM-CSF and VEGF) in HASMCs from smokers and COPD patients. Similar to the findings against inflammation and ALI, SIRT1 and p38 MAPK are regarded as therapeutic targets of resveratrol in lipoteichoic acid (LTA)- or TNF-α-stimulated HASMC models (Knobloch et al., 2010; Knobloch et al., 2014). The abovementioned therapeutic effects and mechanisms of resveratrol have also been demonstrated in animal models (Chen et al., 2016; Wang et al., 2017a). Together, these findings suggest that six main compounds can regulate NF-κB, UPR, TGF-β, MAPK and SIRT1 pathways to inhibit COPD in different cell and animal models (Table 3).

It is now clear that many elements of the innate and adaptive immune response participate in the differentiation and activation of fibroblasts. The pathogenesis of PF is related to adaptive and innate immune activation, inflammation, epithelial/endothelial damage, EMT and cell apoptosis. Specifically, the activation of TGF-β or NF-κB pathway is the primary factor driving the progression of PF (Kitani et al., 2003; Wynn and Ramalingam, 2012). Some natural products, such as β-sitosterol, quercetin, ferulic acid, hesperidin, and EGb761 from various herbs, inhibit PF by downregulating TGF-β. β-sitosterol and ferulic acid suppress EMT and reduce extracellular matrix (ECM) through the TGF-β/Smad-dependent signaling pathways (Park et al., 2019; Ali et al., 2021). Quercetin suppresses Akt/mammalian target of rapamycin (mTOR) pathway in TGF-β-mediated responses and reduces fibrotic factors, such as collagen I, collagen III, and IL-6 (Xiao et al., 2020b). Another study has reported that quercetin enhances the expression of caveolin1 (CAV1), the cell membrane lipid raft and a protective factor for PF, to inhibit ligand-induced apoptosis in fibroblasts (Hohmann et al., 2019). For other bioactive compounds, hesperidin and EGb761 improve the progression of PF by mediating the proinflammatory cytokines and apoptosis-related proteins via the crosstalk of NF-κB and TGF-β pathways (Zhou et al., 2019; Pan et al., 2020).

Hyperoside inhibits the EMT via the regulation of the Akt/GSK3β pathway (Huang et al., 2020). Ellagic acid suppresses ECM accumulation by regulating the Wnt pathway (Li et al., 2021). EGCG reduces the production of cytokines through the Nrf-2/HO-1 pathway (Sriram et al., 2009; You et al., 2014). Galangin and isorhamnetin attenuate EMT and inflammatory damage in bleomycin or TGF-β-induced PF models (Zheng et al., 2019; Wang et al., 2020b). Kaempferol promotes autophagy in the therapeutic effects on PF (Liu et al., 2019b). Resveratrol regulates miR-21/Smad7 to alleviate serious PF symptoms (Wang et al., 2018b). Rosmarinic acid targets miR-19b-3p/MYPT1 to relieve the pulmonary fibrosis caused by radiotherapy (Zhang et al., 2020). Collectively, these results indicate that these bioactive compounds can reduce EMT and ECM deposition to inhibit progressive lung fibrosis by regulating TGF-β, Akt/GSK3β, Nrf-2/HO-1, or microRNA-mediated pathways (Table 4).

Asthma is associated with the activation of IgE-mediated mast cells and eosinophilic inflammation. Inhaled corticosteroids which have a therapeutic effect on allergic reactions and sensitivity of type 2 inflammation, are the cornerstone treatment for asthma. Airway inflammation and remodeling, and airway hyperresponsiveness (AHR) promote the pathogenesis of asthma (Mishra et al., 2018). Naïve CD4 T cells are exposed to antigens and differentiate into various T helper (Th) cell types (e.g., Th1, Th2, Th17). Th2 cells play an important role in disease pathogenesis and progression (Chen and Kolls, 2013; Gaurav and Agrawal, 2013). However, neutrophilic inflammation has also been observed during asthma exacerbations as well asc in severe asthma patients (Ray and Kolls, 2017). Through the literature search, natural products from 10 different medical plants have a good inhibitory effect on the inflammation based on eosinophils and neutrophils in asthma. Unsurprisingly, the dysregulation of the NF-κB and MAPK signaling pathways associated with inflammation and immune response, plays a major role in asthma (Freund-Michel and Frossard, 2008; Zhang et al., 2013). Rosmarinic acid, tussilagone, formononetin, galangin, ellagic acid, and ginkgolide B can downregulate the levels of histamine, ovalbumin (OVA)-specific IgE, Th2 cytokines, and chemokines (IL-4, IL-5, IL-13, CCL5, and CCL11) in serum and bronchial alveolar lavage fluid through the suppression of the NF-κB and MAPK signaling pathways (Chu et al., 2011; Alves et al., 2013; Kim et al., 2013; Zha et al., 2013; Zhou et al., 2014; Liang et al., 2016a; Liang et al., 2016b; Henry et al., 2020; Jin et al., 2020; Yi et al., 2020). EGCG inhibits MMP-9 production, ROS generation, and EMT to reduce airway remodeling by upregulating PTEN (Kim et al., 2006; Yang et al., 2018). Kaempferol ameliorates airway hyperplasia and hypertrophy via the Syk-PLCγ and PKCμ-ERK-cPLA2-COX2 and NF-κB signaling pathways (Gong et al., 2012; Shin et al., 2015; Molitorisova et al., 2021). Glabridin, β-sitosterol and quercetin can suppress the level of serum IgE, TNF-α, IL-4, and IL-5, but the mechanism has not been thoroughly explored (Rogerio et al., 2007; Mahajan and Mehta, 2011; Dogan et al., 2020). Luteolin inhibits the inflammatory responses and autophagy via the PI3K/Akt/mTOR pathway (Jang et al., 2017; Wang et al., 2021). Taken together, in asthma, these 10 bioactive compounds can inhibit inflammatory reactions and airway remodeling through the MAPK and NF-κB pathways in OVA-induced animal models (Table 5).

Lung cancer is the malignant tumor with the highest mortality rate. It causes 1.6 million deaths every year, but treatment can effectively prolong survival and quality of life (Siegel et al., 2021). TCM treatment can effectively improve the quality of life and survival time of patients with advanced lung cancer with or without conventional therapy (Sun et al., 2019; Jiang et al., 2016b; Xu et al., 2011). Active components of TCM participate in the treatment of lung cancer through the regulation of multiple pathways (Table 6). Ursolic acid and β-sitosterol show a good lung cancer-inhibiting effect via the TGF-β/Smad pathway (Ruan et al., 2019; Sundarraj et al., 2012; Wang et al., 2017b). Caffeic acid and sanguinarine enhance the antiproliferative effect of paclitaxel in lung cancer A549 and H1299 cells (Lin et al., 2012). Sanguinarine can target NF-κB pathway-mediated autophagy and mitophagy to block lung cancer progression (Yu et al., 2020b). Meanwhile, the p53 protein is a transcription factor that inhibits cell proliferation or survival, acting as a key tumor suppressor protein (Skoulidis and Heymach, 2019). Loss or mutant of p53 induces lung cancer with shortened latency and increases rapid progression and poor prognosis (Donehower et al., 2019). Natural products such as hyperoside, resveratrol, liquiritin, and formononetin have a good effect on improving the antitumor function of p53 and inducing the apoptosis of tumor cells. Hyperoside increases Caspase-9/Caspase-3 activation to induce apoptosis in in vitro and in vivo models of A549 and H1975 cells (Liu et al., 2016; Lü, 2016). Resveratrol decreases antiapoptotic factors, Bcl-2 and Bcl-xl and the levels of MMP2, and MMP9 by upregulating the p53/HO-1 pathways against lung cancer (Liu et al., 2010; Rasheduzzaman et al., 2018; Li et al., 2019). Liquiritin decreases the expression levels of PCNA, p-PTEN, caspase family, and PARP (Zhou and Ho, 2014). Formononetin promotes Mcl-1 ubiquitination and degradation via Fbw7 to enhance the EGFR-TKI sensitivity (Yang et al., 2014; Yu et al., 2020c). The PI3K/Akt signaling pathway is an important dysregulated pathway in tumorigenesis, which controls lung cancer growth, metabolism, motility, and other key cellular processes (Janku et al., 2018). Isorhamnetin and apigenin inhibit EMT and decrease invasion by inhibiting Akt activation (Chang et al., 2018b; Luo et al., 2019). Moracin N induces autophagy mTOR signaling pathway (Gao et al., 2020). Furthermore, isorhamnetin as a potential application in adjuvant radiotherapy inhibits the activation of NF-κB and increases the expression of IL-13 (Du et al., 2020). Resveratrol and ellagic acid promote lung cancer cell apoptosis via the PI3K/Akt signaling pathway (Liu et al., 2018b; Li et al., 2019). Amygdalin downregulates the phosphorylation of Akt to inhibit invasion and migration of H1299 and PA cells (Qian et al., 2015). Inactivation of STAT3 is a target for increasing cisplatin sensitivity in lung cancer treatment, galangin, and laricitrin are STAT3 inhibitors in adjuvant chemotherapy (Chang et al., 2016a; Chang et al., 2016b; Yu et al., 2018). Oleanolic acid enhances mitophagy through the PINK1/Parkin axis in A549 cells (Castrejón-Jiménez et al., 2019). Rosmarinic acid could reverse the cisplatin resistance by inhibiting the expression of P-gp, MDR1, and MAPK pathways and plays a key role in the treatment of non-small cell lung cancer (NSCLC) (Liao et al., 2020). EGCG from Eriobotrya japonica (Thunb.) Lindl. and Ginkgo biloba L. can suppress the levels of Axl and Tyro three to reduce the resistance to platinum (Kim and Lee, 2014). Ginkgolide B and glabridin from Ginkgo biloba L. have inhibitory effects on autophagy and angiogenesis, mediated by Beclin-1 or FAK/Src complex, respectively (Tsai et al., 2011; Wang et al., 2020c). In H1975 cell model, ursolic acid inhibits the Wnt/β-catenin pathway to suppress proliferation and induce apoptosis (Yang et al., 2019). As a cisplatin sensitizing agent, ginkgetin enhances the ferroptosis-mediated disruption of the Nrf2/HO-1 axis (Lou et al., 2021). Kaempferol downregulates Nrf2 and upregulates miR-340 to induce apoptosis and autophagy (Han et al., 2018; Fouzder et al., 2021). As for quercetin, it can target aurora B or miR-16-5p/WEE1 pathways to inhibit lung cancer progression and enhance the radiosensitivity of NSCLC cells (Xingyu et al., 2016; Wang et al., 2020d). Hesperidin exhibits antiproliferative and apoptosis induction effects by regulating the miR-132/ZEB2 signaling pathway (Birsu Cincin et al., 2015; Tan et al., 2020). Luteolin inhibits cell proliferation and induces apoptosis via miR-34a-5p targeting MDM4 and RhoA (Jiang et al., 2018; Masraksa et al., 2020). Taken together, these results demonstrate that these bioactive compounds have anticancer effects by targeting multiple pathways, including NF-κB, p53, TGF-β, or miRNAs (Table 6).

Collectively, the network of bioactive compounds, targets, signal pathways, and different pulmonary diseases is visualized in Figure 2. These bioactive compounds, such as isorhamnetin, formononetin, resveratrol, and galangin are active substances of types of saponins, flavonoids, and alkaloids, which can regulate different key targets (NF-κB, PI3K/Akt, Nrf-2, NLRP3) to regulate cytokine production, oxidative stress or chemotherapy sensitivity against a series of lung-related diseases.