Inflammation – the Link to All Disease
There is no doubt that inflammation is the underlying driver that touches the most number of patients. Every pathological condition in existence, whether it be a joint condition, mood disorders, cardiovascular disease or cancer holds some sort of inflammatory link. These days, all too many patients report chronic pain syndromes as a consequence of uncontrolled inflammation which can be ruling and ruining their lives. Imagine joints so painful you can’t do simply daily tasks such as combing your hair, picking up your newborn baby or carrying a bag of groceries. We are all too familiar with patients who have endured failed attempts to escape the prisons of their inflammatory condition. What if this is because the traditional approaches to remedy chronic inflammatory conditions have been pursuing an incomplete story? In recent years, understanding of the mechanisms of inflammation have advanced; with the identification of new key targets that can be modulated by natural medicines to interrupt the inflammatory network and allow the natural healing process to unfold.
Inflammation is Not Just the Result of Continual Onset
Despite its negative connotations, inflammation is in fact a formidable ally, representing the body’s natural response to neutralise a threat and restore function. When discussed, inflammation is quite often used as an all-inclusive term, with no discrimination for all of the complicated events that occur during this process. However, at a macroscopic level the inflammatory process consists of two distinct phases – the onset, during which time tissue-resident macrophages sense damage and attract neutrophils to the site to mount the inflammatory response in an attempt to remove the threat. The second phase is the inflammatory resolution – the clearance and efflux of immune cells from the site that allow the tissue to repair. Successful resolution is critical to prevent the development of chronic pain and inflammatory disorders, and new evidence is emerging that shows it is not how often or extensive an acute inflammatory reaction starts (i.e. the onset), which is where traditional anti-inflammatory treatment has focused, rather it is how effectively and quickly it resolves that determines whether the inflammatory battle produces a detrimental or favourable outcome for the patient.
Resolution is the Solution
Traditionally, resolution was thought to be a passive process resulting from the eventual dissipation of pro-inflammatory signals. We now realise, it is an active process the hallmark of which is the apoptosis of neutrophils which occurs once the insult has been contained. Both neutrophils and macrophages secrete chemical messengers to help co-ordinate the transition to resolution. Like a conductor directing an orchestra to change the style of music from intense and dramatic to soft and calm, these chemical messengers command the immune system to switch its tunes from high intensity inflammation to the healing sounds of resolution.
The chemical messengers providing the instruction to begin resolution are metabolites of long chain polyunsaturated fatty acids, dubbed specialised pro-resolving mediators (SPMs). Arachidonic acid is the precursor for one series of SPMs – lipoxins, whilst eicosapentaenoic acid (EPA) provides resolvins and docosahexaenoic acid (DHA) is the source of protectins and maresins, adding further weight to the use of fish oil in inflammatory conditions. In fact, studies have demonstrated a dose of 2.4 – 4 g/day EPA/DHA will obtain biologically active plasma concentration levels of SPMs.[1],[2] All SPMs play a critical role in promoting the resolution of inflammation, through inhibiting further recruitment of inflammatory cells, causing the phagocytosis of neutrophils, and promotion of immune cell clearance from the site.[3] These lipid mediators are so potent that only picrogram per millilitre concentrations are needed – in this way SPM activity could be likened to that of hormones, only with the specific action of resolving the inflammatory response.
When Fish Oil Isn’t the Only Answer
If it is as simple as prescribing fish oil to resolve inflammation, why are we not achieving this outcome with many of our patients? Sound scientific and clinical evidence supports the known mechanisms of action of fish oil in promoting the production of anti-inflammatory prostaglandins, and now with the newer evidence showing its keystone role in the effective resolution of inflammation, it would seem that fish oil is the ultimate answer.
However, the likely reason we are not seeing these results with many of our patients is because we have not eliminated the underlying factors that the immune system identifies as the threat, thus chronic inflammation ensues. Until the driver is determined and eliminated, fish oil is battling against a tsunami of undermining factors. Some of the more commonly identified perpetuators of inflammation include oxidative stress, persistent pathogens, unrepaired tissue damage (which typically occurs in autoimmune conditions), insulin resistance, persistent allergens, leaky gut, dysbiosis and, an interesting paradox, the chronic use of non-steroidal anti-inflammatories (NSAIDs).[4],[5],[6].[7]
There is Nothing to See Here Inflammation, Move Along
Acute inflammation occurs when the insult is self-limiting and SPMs effectively promote the transition to resolution. During acute inflammation there still is ‘collateral damage’ from the response and the hallmarks of inflammation (redness, heat, swelling, pain, and loss of function) occur. Therefore, even patients with acute inflammation would benefit from anti-inflammatory support to help manage their symptoms until resolution occurs. Alternatively, if the trigger remains or there is a lack of successful resolution, the process moves down another pathway causing chronic inflammation.
Inflammation is Broader Than Once Thought
Assuming we have addressed the drivers underlying inflammation and are providing adequate EPA/DHA to orchestrate resolution, we still need to provide relief during the onset phase of inflammation to make life more bearable for patients. Up until now, clinicians have almost exclusively focused on treating downstream sections of the inflammatory cascade, such as prostaglandins, and nuclear factor kappa B (NFκB). Whilst targeting prostaglandins, NFκB and its downstream cytokines has achieved some level of success, far greater benefit may occur by addressing more components of the process. Functionally, the inflammatory response can be seen as a process with five points of intervention: stressors, sensors, mediators, transcription factors and mediators.[8]
Stressors Strike the Match
Stressors represent the original starting point for all inflammation, with numerous stressors identified beyond the common culprits of infection and tissue damage from an injury. Exogenous stimuli include infection, allergens and toxins, whereas endogenous triggers come from signals created in response to damaged cells/tissues and malfunctioning physiology, such as oxidative stress.[9] Through pattern recognition receptors (PRR), the body recognises certain molecular structures of infectious organisms (PAMPS) and cell damage signals (DAMPs), which act as key triggers of inflammation. Other triggers include advanced glycation end products (AGEs) and oxidised lipoproteins.[10],[11],[12] Ultimately, the stressor needs to be removed or it is like a constant distress signal setting off the inflammatory tirade, perpetuating inflammation and preventing resolution.
Receptors Receive the Distress Signal
There are several key receptors that detect stressors and set the inflammatory wheels in motion. Again, this is part of a healthy protective process, however has been shown to be overactive in chronic inflammatory diseases. Toll-like receptors (TLRs) are one example of a receptor that specifically recognise the molecular patterns of extracellular PAMPs and DAMPs[13] and as the name suggests, AGEs are a ligand for receptor for advanced glycation end products (RAGE).[14] There is increased RAGE expression in many chronic inflammatory diseases and in a self-perpetuating manner, inflammation promotes further expression of RAGE.[15],[16],[17] Inflammasomes are intracellular receptors which are created from the assembly of three proteins that, once formed, triggers the intracellular inflammatory response. Inflammasomes are vulnerable to activation by a wide variety of stressors such as PAMPs, DAMPs, toxins, oxidative stress, hyperglycaemia and uric acid crystals (e.g. such as in gout).
Damping receptor activity is a key strategy to attenuate inflammation, as this is a summation point where multiple inputs converge, and where self-perpetuating cycles are established. Therefore it is critical to address receptor activity to prevent the downstream amplification of inflammation signalling.
Mediators and Transcription Factors Are Like Soldiers That Carry Out Orders
Similar to sensors, there are several intracellular signalling pathways that initiate the inflammatory response. Clinically, it is not critical to know the finer details of these multifaceted networks, but useful to recognise some key targets, that if addressed, will disable inflammatory signalling.
Mitogen-activated protein kinases (MAPK) are a group of intracellular protein kinases that activate the transcription factor activator protein 1 (AP-1). IκB kinase (IKK) is another key mediator of inflammation which activates NFκB. TANK-binding kinase-1 (TBK-1) can also activate NF-kB and another pro-inflammatory transcription factor: interferon regulatory factor 3 (IRF3).[18] The three transcription factors, when activated, move from the cytosol into the nucleus and bind to specific sections of the DNA to promote pro-inflammatory gene expression. These pathways re-inforce each other to amplify and prolong the inflammatory response.[19] Clinically, we have up until this point employed effective remedies to dampen NFκB, however, we can now see that is only one chapter of the entire story and we require agents to also mitigate AP-1 and IRF3 for the best possible results.
Effectors Drive the Damage
The activity of the three abovementioned transcription factor results in the expression of numerous pro-inflammatory mediators. Activation of NFkB initiates the release of cytokines such as nitric oxide (NO), tumour necrosis factor alpha (TNF-α), various interleukins (IL) and the specific matrix metalloproteinases (MMP-9)[20] involved in tissue damage. The activation of AP-1 leads to up-regulation of cyclooxygenase-2 (COX-2), IL-8, interferon (IFN)-β, MMP-1 and MMP-3, whilst IRF3 induces the expression of IFN-β and IFN-inducible genes.[21] Collectively, the activity of the three transcription factors release a broad spectrum of inflammatory agents driving symptoms. MMP activity can be particularly problematic as these enzymes can break down tissue and release more DAMPs, thereby creating more stressors to perpetuate the chronic inflammatory cycle.
Phytochemicals to Hit Key Targets
Fortunately, addressing the multiple points of the inflammatory cascade doesn’t mean prescribing multiple products, one for each target. The ingredients in BCM-95™ Turmeric & Devil’s Claw to Treat Chronic Inflammation were carefully selected based on evidence that shows, together, they broadly impact the entire inflammatory network. This is one of the many benefits of phytochemicals, in that (unlike pharmaceutical medications) they don’t act solely on one enzyme or pathway, which can induce damaging consequences. Instead, they influence a broader spectrum of targets to produce healthy therapeutic outcomes. As an example, curcumin has been shown to address all areas of the cascade, including reducing levels of DAMPs (a stressor),[22] inhibiting inflammasome assembly[23] and RAGE[24] (receptor), reducing MAPK[25] and all three transcription factors NFkB, AP-1 and IRF3[26] and consequently, has been linked with lower levels of effectors/inflammatory end products.[27],[28], [29] Similarly, boswellia and devil’s claw are two other phytochemicals that have been shown to impact several areas of the inflammatory network, such as reducing MAPK, AP-1 and NFkB, with devil’s claw also demonstrating potent analgesic effects in clinical trials.[30],[31],[32] Jamaica dogwood has been used traditionally for its analgesic effects and its isoflavonoid constituents, which have demonstrated anxiolytic, mild sedative and spasmolytic properties.[33],[34]
Putting the Brakes on Pain Signalling
Unfortunately, the majority of patients with chronic inflammatory disease will suffer some degree of pain as a consequence of the physiological changes this processes induces. Pain signals are driven by inflammatory mediators and other triggers activating peripheral receptors (nociceptors), which transmit pain messages along the ascending pathways of the central nervous system (CNS). These impulses trigger the release of glutamate at the dorsal horn of the spinal cord, via N-methyl-D-aspartate (NMDA) receptors.[35] To dampen this heightened pain signalling, the CNS is equipped with inhibitory circuits via the descending pathway, with gamma aminobutyric acid (GABA) acting as the chief inhibitory neurotransmitter.[36] Key drivers of nociception activity are inflammation, acidity, ischaemia, oxidative stress, mitochondrial dysfunction, nerve dysfunction and injury.[37],[38],[39],[40] Therefore, whilst it is important to address inflammation, we also need to be mindful of the need to provide patients with symptom relief to enable them to resume better functionality, not to mention enjoyment of life.
Meta Mag® – Magnesium Bisglycinate, Corydalis and California Poppy for Pain
Already a favoured nutrient for the treatment of many pain-related pathologies, the clinical data supporting magnesium for the management of pain disorders is continually mounting.[41],[42],[43],[44] Magnesium is not only considered an NMDA antagonist,[45] due to its ability to inhibit glutamate binding, it also indirectly reduces many nociceptor stimulants such as acid accumulation,[46] inflammation[47] and mitochondrial dysfunction.[48] These actions work nicely alongside the alkaloid compounds dehydrocorybulbine (DHCB) and L-tetrahydropalmatine (1-THP) found in Corydalis ambigua (Corydalis), which mediates its analgesic effects in both inflammatory and neuropathic pain.[49] In a recent clinical trial, 1.8 g/day of cordydalis for 12 weeks was found to be comparable to the NSAID, diclofenac sodium, in efficacy for the treatment of osteoarthritis.[50] Another herb with a long history of traditional use for pain relief is Eschscholzia californica (California poppy), which also works to promote calm sleep[51] via its affinity for GABA receptors.[52],[53] In two controlled clinical trials, the combination of corydalis and California poppy normalised disturbed sleeping behaviour without evidence of hang-over effects or addiction.[54]
Natural Treatment for Acute Pain and Chronic Inflammation
The most effective approach to the management of pain and inflammation is firstly to find the ‘off’ switch, by identifying and eliminating the many potential drivers such as insulin resistance, oxidative stress, infection and tissue damage. Next is to ensure you provide your patients with adequate symptomatic pain relief to help restore functionality and quality of life. The use of High Potency Anti-inflammatory Herbs along with Meta Mag® – Magnesium Bisglycinate, Corydalis and California poppy for Pain provides excellent relief for acute pain and inflammation. To prevent the transition from acute to chronic inflammation, High Purity, Low Reflux, Concentrated Fish Oil provides the precursor substrates for the tissues to synthesise the SPMs to promote resolution. If your patient is suffering from chronic inflammation then recommend BCM-95™ Turmeric & Devil’s Claw to Treat Chronic Inflammation in place of High Potency Anti-inflammatory Herbs as it is formulated to treat chronic upstream activation and mitigate tissue damage which may drive chronic inflammation.
This multifaceted approach proved highly successful in turning around patients’ lives in the Health Wold research clinic. These individuals can now do the things they couldn’t do for a long time, but dearly wished to: comb their hair, cast a fishing rod, go grocery shopping by themselves and pick up and hug their children.
Article provided by Metagenics.
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