Introduction
Inflammation is an evolutionarily conserved response characterized by the activation of immune and other somatic cells that provide protection from microorganisms, toxins and infections. This is typically characterized by the elimination of pathogens and the promotion of tissue repair and recovery (1,2).
When the process proceeds in a healthy body the process of inflammation is temporal restricted; it occurs when a threat is present and resolves once the threat has passed (3). Notably, the presence of select social, psychological, environmental and biological factors has been shown to inhibit the resolution of acute inflammation. This may result in a state of low-grade, non-infective systemic chronic inflammation characterized by the activation of immune components that are often distinct from those engaged during an acute immune response (4,5). For healthcare providers, it is key to understand both acute and chronic inflammatory processes.
The below perspective and collection of data come from my clinical experience of managing 3 different patients that responded quickly to what appeared to by an anaphylactic response to something in their diet. One case was directly observed in a classroom setting. Two other cases were done by phone as the patients were reacting to their allergens. Two other practitioners have shared case studies with the author that were successfully treated with Echinacea spp. and Taraxacum officinalis tincture for a total of just under a dozen cases that were postulated to be anaphylactic responses. Doses used are 5 ml of each extract every 20 minutes, for a total of 10 mL every 20 minutes until symptoms are resolved. In all three cases the dosing was done for a total of 3 doses.
Due to the focus on the previously mentioned clinical work this discussion will focus on the resolution of acute inflammation in hypersensitivities. The main pharmacological targets we will discuss are peroxisome proliferator-activated receptor gamma (PPARĪ³) and cannabinoid receptor type 2 (CB2). Keep in mind that both pharmacological sites below are also potentially useful for chronic inflammation.
Hypersensitivities
Allergies (also known as āhypersensitivitiesā) are due to overreactions of the immune system to substances that do not necessarily elicit immune responses in the majority of people. Hypersensitivities are grouped into four types; I, II, III and IV. These groupings are based on which white blood cells (WBCs) and tissues of the immune system are activated and how long it takes for a reaction to occur.
The two types of hypersensitivities that are referred to as allergies, are type I or āimmediateā hypersensitivities, and type IV or delayed type hypersensitivities (DTH).
The cells and pathways involved in type 1 hypersensitivities are mast cells, IgE and the release of histamine. An antigen induces the formation of IgE antibodies, in individuals with an atopic predisposition, via B lymphocytes. Reactions occur only after a requisite initial exposure, in which the primed mast cells bind IgE and start the degranulation process. This commonly involves the respiratory, gastrointestinal and/or the skin and occurs within minutes to hours.
In type IV hypersensitivities, or DTH, instead of involvement of the antibody IgE, T lymphocytes are involved and the onset of symptoms take hours to days to appear. CD4+ , T helper cells, in response to haptens (small antigens), release cytokines/chemokines which can recruit macrophages to a site (such as in the tuberculin-type response due to a TB test) inducing local inflammation. In the case of Type IV interactions the immune system does not need to be primed but does go through a sensitization phase. The outcome is acute inflammation and possibly edema. The skin is often the obvious site of DTH reactions (redness, swelling, hardening of the skin, rash, dermatitis).
The PPARĪ³ receptor
The PPARs constitute a set of three receptor sub-types which are members of the nuclear receptor superfamily of ligand-activated transcription factors. They are encoded by distinct genes that function as lipid sensors that regulate gene expression in many metabolically active tissues (6). The PPARs, so named because in early research it was found that PPAR-Ī“ stimulation resulted in the increase in peroxisomes, have a significant role in cellular energy balance, fuel utilization, the metabolism of fatty acids and other lipids, the generation and remodeling of adipose tissue and fibrotic and hypertrophic responses in the heart and vascular wall. Many of these actions are via interactions with nuclear factors such as NFĪŗB, NFAT and activator protein 1 (AP-1), thus modulating expression of pro-inflammatory cytokines and adhesion molecules, and altering cell signaling pathways (7,8). Thus, PPARs, in response to stressors, play a role in the complex orchestration of adaptive cellular physiology working in a concerted mode with the vitamin D receptor and the retinoic acid receptor (RXR). PPARs have been found to be involved in inflammation and carcinogenesis, and other immune activity. Thus, many pharmaceutical companies have been involved in PPAR research in search of the perfect ligand in areas such as diabetes, obesity, cardiovascular disease and immunology with drug development in mind.
The endogenous ligands to the PPAR sites were originally unknown, earning the PPARs the name āorphan nuclear receptorsā. Key to this discussion, PPARĪ³ plays a significant role in allergic response, specifically PPARĪ³ (9-15). The high-affinity IgE receptor Fc epsilon RI (FcĪµRI), found on mast cells and basophils, plays a central role in IgE-mediated inflammatory reactions. PPARĪ³ agonists have been shown to inhibit the expression of CD117 (tyrosine-protein kinase KIT orĀ mast/stem cell growth factor receptor) and FcĪµRIĪ± (9,11), and the maturation of bone marrowāderived mast cells, as well as inhibiting the formation of granules and reducing the expression of Ī²āhexosaminidase (a marker of mast cell degranulation) and induce mast cell progenitor apoptosis (9). Finally a reduction in mast cell histamine content (15), histamine release (11,15) and suppression of body temperature increase in anaphylaxis models has been documented (12). Human trials of PPARĪ³ agonist on patients with atopic dermatitis has demonstrated a decreased total body surface area involvement, severity of lesions, and number of flares with PPARĪ³ agonists (16). In allergic asthmatic patients a down-regulation of PPARĪ³ expression has been observed in lung tissue (17,18) and noted to be a potential factor in dysregulation of pulmonary homeostasis (17).Ā While in steroid resistant asthmatic smokers an inhaled PPARĪ³ agonist has shown improvements in lung function superior to steroid inhalation (19).
Human data in a month long double-blind randomized controlled trial, with a PPARĪ³ agonist vs. placebo reduced the late asthmatic response by 15% and a reduction of exhaled nitric oxide by 14% (20). Another double blind RCT of a PPARĪ³ agonist in severe asthmatic patients was found not to have a positive outcome (21). While PPARĪ³ as a pharmacological target has strong preclinical data, the evidence in clinical trials is not robust. It may be that PPARĪ³ needs concurrent support by engaging other pharmacological targets within a physiological network of allergic reactions. Intriguingly, PPARĪ³ is now considered part of the endocannabinoid system (22-26).
The CB2 receptor
The CB2 receptor is a G protein-coupled receptor located on T & B lymphocytes, as well as natural killer cells, macrophages, neutrophils and mast cells (27). The CB2 receptor has been found to play a significant role in immune dynamics including the resolution of inflammation, cancer, atherosclerosis, osteoporosis and chronic pain (28). The CB2 expression in lymph nodes and spleen is higher than in peripheral blood cells and is different in various immune cell populations; B cells > NK cells > monocytes > neutrophils > CD8 T-cells > CD4 T-cells (29,30).
CB2 is a particular attractive for cannabinoid agonists selective for this site because of a paucity of psychomimetic activity. Nonetheless, in the face of remarkable volumes of preclinical data, only one CB2 potential drug molecule (cannabinor) has made it to phase II clinical trials (31). Other human data comes from marijuana smokers provide insight as to the effects of CB2 ligands on immune function. Lung alveolar macrophages removed from marijuana smokers have diminished capacity for the generation of TNF, gmCSF and IL-6 (inflammatory cytokines) (32).
Notably, CB2 ligands have demonstrated the inhibition of FcĪµRI-induced degranulation in mast cells in a concentration dependent manner. GPR55 (a putative CB3 receptor) also appears to show the same effect. CB1 appears not to have a role in inhibition of mast cell degranulation (33).
CB2 agonist have also shown a role in the retention of immature B cells in the bone marrow (34) and demonstrated a significant decrease in CXCR4 (a chemotactic chemokine) in bone marrow cells (34). CB2 is involved in the inhibition of lymphocyte recovery after bone marrow transplantation as well (35).
Other data suggest that cannabinoids can inhibit the production of TNF and other cytokines by several different pathways, some independent of cannabinoid receptors (27). Conversely, cannabinoids have also been shown to increase the production of cytokines (including TNF, IL-1, IL-6, and IL-10) if administered with appropriate immune stimulation (bacteria or antigens) (27) or, in some cases, without immune stimulation (36). Challenging a common misconception of CB2, this strongly suggest true immunomodulation and not simple immunosuppression.
The herbs
The use of herbal remedies as a substitute for medical care is growing rapidly (37). An observation by this author is that in the United States, due to lack of s public health care system, every recession is accompanied by an increase in the sales of natural products. This is likely due to health insurance being tied to employment. As U.S. citizens lose their jobs, they also lose their health insurance.
Intriguingly, laboratory studies suggest that in some cases the overall pharmacological effects and therapeutic efficacies from medicinal plants may not derive from a single compound but from several compounds generating synergic activity (38-42). Synergy as a pharmacological construct, is often cited as a general mode for the biological activity of these compounds (38-43).
Preparations of Echinacea spp., have been used for more than a century for treatment of a variety of infections (44). More than 3 million physician prescriptions for Echinacea preparations are written annually in Germany (45) where there are more than 800 Echinacea products on the market (46). Most preparations are derived from the aerial parts of E. purpurea and underground parts of E. purpurea, E. angustifolia, or E. pallida (47).
Although controversial, the Echinacea spp. are often used interchangeably for the treatment of colds, flus, respiratory infections, and inflammations (48). Echinacea is documented to have immunostimulating, anti-viral, antibacterial, antifungal, insecticidal properties and anti-inflammatory properties (47,49).
Despite some negative outcomes in a few clinical trials using echinacea to treat upper respiratory infections, there are enough positive data in the human trials to offset the negative results. As a result, the meta-analyses that have been performed suggest that Echinacea products are effective (50-53).Ā A Cochrane review reports some Echinacea preparations may be better than placebo and that the majority of the Echinacea studies demonstrate positive results (51). A meta-analysis by Schoop et al. (52), reports that standardized extracts of Echinacea were effective in the prevention of symptoms of the common cold as compared with placebo. Islam and Carter (53) conclude that there is a beneficial effect from Echinacea, but also suggest that differences in products and doses make evaluation challenging (51). Linde et al. (50) suggest that there is evidence, although inconsistent, that Echinacea is effective in treating URIs. A meta-analysis of studies with children Ā (< 18 y/o) found that Echinacea reduces the incidence of URIs by 40% (54). Finally, the most recent meta-analysis finds that the evidence supports Echinaceaās benefit in decreasing the incidence and duration of the common cold in adults (55).
Echinaceaās effectiveness is believed to be related more to the enhancement of innate immunity, rather than antimicrobial activity (49,56) The stimulation of innate immunity by Echinacea extracts are well established (57-65). Studies have reported that echinacea extracts have the ability to activate human phagocytic function both in vitro and in vivo (58,59,61,66-68). Additionally, the plant has shown ex vivo immune stimulation in human immunodeficiency disorders (60). The immunomodulatory effects are believed to be mediated by induction of cytokines from macrophages and antioxidant activity (49,69). However, some people, mostly those who are not experienced with the clinical use of echinacea,Ā believe that echinacea products are simple immunostimulating and as such, would be contraindicated in an attenuating an acute immune response. Only recently has basic research supported a biphasic response, clinicians who have extensive experience with echinacea preparations have been aware of this for many decades.
Echinacea spp. as immunomodulators
The search for endogenous ligands for the cannabinoid receptors has led to the discovery of several polyunsaturated compounds derived from fatty acids, mostly arachidonic acid (70). Ā These fatty alkylamides, although not as widespread as other classes of natural products, are relatively abundant in plants, and occur in a variety of families, including the Asteraceae, Brassicaceae, Leguminosae, Piperaceae, and Rutaceae (71). Examples of plant species containing alkylamides similar to those of Echinacea spp. can be found in Spilanthes and Zanthoxylum species (28).
The alkylamides found in echinacea species and other medicinal plants, have been of pharmacological interest since humans first noted the tingling and numbing effect from chewing plants rich in these compounds (72). The anesthetizingĀ tingling of these compounds is associated with activation of tactile and thermal trigeminal neurons (73). This property was utilized by native Americans (74) and eventually by physicians in the early 20th century for a variety of purposes including toothache and infections (75). Alkylamides were later recognized as insecticidal by a number of researchers (72,76-78) but eventually interest in these compounds waned. Nevertheless, these fatty acid derivatives have become a subject of renewed interest in the last few decades due to their recent identification as cannabinoid ligands (28,79-81).
The endogenous cannabinoid ligands are the fatty acid metabolites, known as eicosanoids (82). These endocannabinoids (e.g. anandamide from the Sanskrit term “ananda,” meaning bliss and 2-arachidonoyl glycerol) are structurally similar to the alkylamides, which are also fatty acid derivatives, and show nanomolar affinity for the type-2 cannabinoid receptor (CB2).
The affinity of the alkylamides for the CB2 are in the same range as the endogenous ligand anadamide (79). Research supports this, E. purpurea extracts demonstrate that particular isobutylamides modulate TNF mRNA expression in monocytes via CB2 receptors (79,81).Ā Alkylamides binding to CB2 increased IL-8 and monocyte chemoattractant protein, both proinflammatory proteins (79). This may offer new insight into not only the mode of activity of Echinacea, but also immunology. Nadja Cechās group, in collaboration with Bastyr University demonstrated a typical cannabinoid response from both extract and alkylamides of Echinacea; select isobutylamides from E. purpureaĀ inhibited IL-2 expression in T-helper cells (83). Additionally, recent work demonstrates a TH-biasing effect, in which TH1-cell activity is suppressed and TH2-cell activity is increased (80). The cannabinoids show the same effect and this makes a case for the treatment of chronic inflammatory diseases by CB2 ligands (27).
Some have suggested since alkamides have anti-inflammatory activity, this is the primary effect of echinacea preparations (84). Anti-inflammatory activity has been verified through the inhibition of cyclooxygenase and 5-lipoxygenase (47) and the inhibition of IL-2 (83). Nonetheless, there is quite a collection of peer-reviewed research that shows immunostimulation by echinacea extracts and its compounds (57-68). Ā
As for echinacea and PPAR activity, in the authorās hands, we observed inhibition of IL-2 via PPARĪ³ activation (85). We also found that a large number of the alkylamides across the spectrum of unsaturation that differentiate this class of compounds activate PPAR (89).Ā
Previous research has also demonstrated that Echinacea extracts inhibit mast cell degranulation. The authors of this research concluded that inhibition of mast cell activation coupled with the well-established inhibition of proinflammatory cytokine effects by alkylamide rich Echinacea extracts suggest utility in allergic diseases (90).
The alkylamides are not the only active constituents. There are other compounds in the Echinacea spp. that deserve mention. Three other constituent groups have shown activity; the hydroxycinnamates (caftaric acid, caffeic acid, chlorogenic acid, cichoric acid, cinnamic acid, cynarin, echinacoside etc.), polysaccharides, and glycoproteins (91,92).
Another phytocompound found in Echinacea, as well as cinnamon, clove, rosemary and black pepper, and such medicinal plants as Bidens pilosa, Angelica archangelica and Apium graveolens, isĪ²-caryophyllene (BCP), a sesquiterpene. BCP is considered a phytocannabinoid as it binds CB2. Research shows that via a CB2 mode of activity BCP has demonstrated significant cardioprotective effects in preclinical research in induced myocardial infarction models. Notably, BCP reduced the myocardial expression of inflammasome proteins including NLRP3, procaspase-1 and pro-IL-1Ī² via TLR4 mediated NF-ĪŗB/MAPK signaling in CB2 dependent manner. Moreover, BCP enhanced the expression of the CB2 receptor and PPARĪ³ and activated myocardial CB2 receptors resulting in the mitigation of oxidative injury (93).
Considering the number of phytochemical families that are active, the explanations of the effect of Echinacea include suggestions that the activity may be due to an entourage effect (85). There has also been in vitro antioxidant activity demonstrated by the hydroxycinnamates for both E. purpurea and E. angustifolia extracts (94,95). However, antioxidant activity will be addressed in the next section on Taraxacum officinale.
Taraxacum officinale
One of the most ubiquitous medicinal plants, Dandelion (Taraxacum officinale) is well-known as a food due to its rich content in nutrients. Although considered by many to be an annoying weed, every traditional culture that has a native Taraxacum species has found medicinal use for this versatile genera (97). Unfortunately, dandelion is often overlooked due to is prevalence. An initial clue into its medicinal properties is provided by the name Taraxacum which is derived from the Greek words ātaraxisā for inflammation and āakeomaiā for curative (98). Ā Ā Ā Ā Ā Moreman (74) reviews use of dandelion by various tribes of the native North American culture shows use various parts of the dandelion for food and medicine. For example, the spring stems and leaves were used as vegetables and eaten to build the blood for conditions such as anemia and as a laxative-tonic, while decoctions of the roots were taken for stomach pain and to produce postpartum milk flow. Infusions of leaf and root were taken for kidney trouble and dropsy and used as a bitter tonic, the flower blossoms were taken for menstrual cramps.
In traditional Chinese medicine Taraxacum mongolicum is thought to have activity in a variety of health benefits (99), this includes clearing heat, especially of the liver and urinary tract and to promote lactation (100). In traditional Ayurvedic medicine T. officinale is used similarly asĀ in TCM and said to be valuable in liver disorders and a useful diuretic (101) and to clear heat (102). An early 19th century reference suggests that Taraxacum was used for chronic inflammation, digestive problems, as well as cirrhosis (103).
Although the diuretic properties are well known and recently observed in the first human trial (104), this brief overview will focus on the immune properties of dandelion.
The anti-inflammatory activity of dandelion is most likely partially due to its antioxidant activity and its hepatic activity. Recall that the liver is a key lymphatic organ with the largest population of fixed macrophages (Kupffer cells) of any bodily tissue and is therefore influential on the reticuloendothelial system and immune response. Much of the traditional use of dandelion has supported hepatic activity for dandelion, indications such as liver and/or gall-bladder inflammation and stasis, cholelithiasis, metabolic toxicity, jaundice, hepatitis, and dyspepsia secondary to deficient bile secretion (105). Medicinal plant preparations in general that have hepatic activity are likely to also influence Kupffer cells, although in varying degrees. This obviously can lead to immune up or down regulation. As a hepatic anti-inflammatory, dandelion, at least in clinical observations, appears to also have a systemic anti-inflammatory effect.Ā Phenolic compounds are believed to provide some of the anti-inflammatory activity (98).
A large portion of the research on the activity of dandelion has focused on the antioxidant activity (99,106-109). Past research reports significant antioxidant activity, typical for polyphenol rich plants, and inhibition of inducible nitric oxide synthase (iNOS), as well as synergic activity with other micro and phyto-nutrients such as the ubiquitous catechins and ascorbate (99,106,107). Sumanth and Rana (108) confirmed an antioxidant effect and observedĀ increases in the levels of superoxide dismutase, catalase and glutathione using a hydroethanolic preparation. Zhu et al (109) using a hydroethanolic extract, confirmed Ranaās results in finding increased superoxide dismutase, catalase, glutathione levels along with peroxidase levels and also found reduced lipid peroxidation. Hu and Kitts (99) demonstrated protection of cells from peroxyl-radical-induced intracellular oxidation speculating that the protection may have been the result of scavenging of intercellular and intracellular peroxyl radicals by a phenolic rich extract from dandelion flowers. This team also showed a synergic effect with Ī±-tocopherol and a 40% ascorbate equivalence which they believed was responsible in regenerating the Ī±-tocopherol. Thus, dandelionās antioxidant activity is established.
Antioxidant activity has generally been accepted to be a mode of activity for immunomodulation (110-112). Both anti-inflammatory and antiallergic properties are known to be induced be particular antioxidants (113). The reduction/oxidation (redox) reactions that are crucial to immune function can lead to tissue damage, allergy and autoimmune diseases if balance in this system is lost.Ā Research has confirmed that polyphenols can make improvements in the overall redox status of immune cells (114). In compromised subjects (aged or diseased) this can lead to enhancements in such functions as chemotaxis capacity, microbicidal activity, lymphoproliferative response to mitogens, interleukin-2 (IL-2) and tumor necrosis factor (TNF alpha) release (111). For example, in preclinical (in vivo) models many of the gallate derivatives have exhibited inhibition of histamine release from mast cells (murine model) (112). Additionally, the catechins are known to significantly inhibit type IV allergies in murine models (110). Finally, kaempferol has shown positive effects on IL-4 and JAK3-dependent responses suggesting that compounds rich in this compound may have positive influence on allergies, autoimmune conditions and cancer (115).
Another pathway where dandelion has exhibited activity is in the nitric oxide (NO) pathway. NO is an important effector molecule that plays a role in the majority of the steps of inflammation, and if unchecked, can also lead to tissue damage, inflammation and is involved in allergic response (116). Taraxacum extracts and individual constituents have demonstrated inhibition of inducible nitric oxide from immune cells (99,117).
Considerations of medicinal plant medicines
It must be kept in mind that many of these effects are based on in vitro and in vivo preclinical research. Regardless, the bottom line is that in the previously mentioned cases the treatments with echinacea and dandelion were effective. From an energetic model of medicine many of the pathways discussed can be seen as leading to a reduction in the āheatā of a system. That is, the inflammatory process is interrupted or reduced and therefore the overall effect of this process can be seen as ācoolingā the inflammatory processes. Considering the combination of E. purpurea extracts and T. officinale extracts we have multiple modes of activity including affecting key messenger molecules (see Table 1). The alkylamides via CB2 may down regulate cytokine production. Additionally, the inhibition of cyclooxygenase and lipoxygenase, as well as antioxidant activity, are likely responsible for the effects in the patients discussed above. Hydroxycinnamates, present in both plants, especially cichoric acid and caffeic acid are some of the most efficient antioxidants from natural sources (118). Additionally, direct activity on mast cell degranulation is a strong possiblity, considering the modes of activity of CB2 and PPARĪ³ and the speed in which these patients recovered from an acute hypersensitivity.
An interesting thought lies in the potential of the improvement in other tissues and biochemical pathways influencing hypersensitivities that extracts of T. officinale radix and E. purpurea radix may have. In other words, this likely served as more than a treatment for downregulating an immune process. Rather, there were likely beneficial effects related to other activities, and other undiscussed constituents of the plants that are still unseen. As the late, great herbalist Michael Moore once said āthe advantage of medicinal plants is that they are broad spectrum and naturally dilute. The disadvantage of medicinal plants is that they are broad spectrum and naturally dilute.ā
| CB2 ligands | PPARĪ³ ligands |
|---|---|
| 1. Anandamide MW 347.3 | 6. 15-deoxy-Ī (12,14)-prostaglandin J2Ā MW 316.4 (fibroblasts activity 7 Ī¼M) |
| 2. 2-arachidonylglycerol MW 378.3 (PPARĪ³) | 7. 13-hydroxyoctadecadienoic acid MW 296.4 |
| 3. Dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide MW 247.3 from Echinacea spp. | 8. 13- oxooctadecadienoic acid MW 294.4 |
| 4. Dodeca-2E, 4E-ene-dienoic acid isobutylamide MW 251.3 from Echinacea spp. | 9. Undeca-2E-ene-8,10-diynoic acid isobutylamide MW 231.3 from Echinacea spp. |
| 5. Dodeca-2E,4E,8Z-trienoic acid isobutylamide MW 249.3 from Echinacea spp. | 10. Hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutylamide MW 303.3 from Echinacea spp. |
b. Compounds 3 & 4 are also PPARĪ³ activators. from 87with Ki of 57 nM and 60 nM (88)
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