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<p>Cupping Therapy: An Analysis of the Effects of Suction on Skin and the Possible Influence on Human</p><p>Health</p><p>Author</p><p>Duane T. Lowe</p><p>Interdisciplinary Pain Management Clinic</p><p>Department of Pain Management</p><p>Madigan Army Medical Center</p><p>Joint Base Lewis-McChord</p><p>9040 Jackson Avenue</p><p>Tacoma, WA 98431</p><p>Corresponding Author:</p><p>Duane T. Lowe</p><p>Interdisciplinary Pain Management Clinic</p><p>Department of Pain Management</p><p>Madigan Army Medical Center</p><p>Joint Base Lewis-McChord</p><p>9040 Jackson Avenue</p><p>Tacoma, WA 98431 USA</p><p>e-mail: duane.t.lowe.civ@mail.mil</p><p>Phone number: 719-571-0345</p><p>Fax: 253-968-0469</p><p>Word Count</p><p>Abstract: 264</p><p>Text: 4267</p><p>References: 2473</p><p>© 2017. This manuscript version is made available under the Elsevier user license</p><p>http://www.elsevier.com/open-access/userlicense/1.0/</p><p>mailto:duane.t.lowe.civ@mail.mil</p><p>Abstract</p><p>Background: Cupping therapy is a traditional therapy that has been employed worldwide for thousands</p><p>of years. The lack of quality clinical studies limits the ability to determine presence or absence of</p><p>claimed efficacy but its long history and continued widespread use advocates for it to not be completely</p><p>discounted.</p><p>Purpose: The goal of this paper is to present the research detailing what is known concerning the</p><p>effects of suction on skin and underlying tissue, and the reaction of the body to that stimulus.</p><p>Understanding the literature on the physiological effects of this mechanical force may help elaborate if</p><p>an explanation for the advertised local and systemic effects of cupping exists.</p><p>Findings: Negative pressure causes stretching of the skin and underlying tissue and dilation of the</p><p>capillaries. This stimulates an increase in tissue blood flow, eventually leading to capillary rupture and</p><p>ecchymosis. Macrophages phagocytize the erythrocytes in the extravascular space which stimulates the</p><p>production of Heme Oxygenase-1 (HO-1) to metabolize the heme. Heme catalysis results in the</p><p>production of carbon monoxide (CO), biliverdin(BV)/bilirubin(BR) and iron. HO-1, BV, BR, and CO has</p><p>been shown to have antioxidant, anti-inflammatory, anti-proliferative, neuromodulatory effects in</p><p>animal and human systems. These substances also stimulate a shift of macrophages to the anti-</p><p>inflammatory M2 phenotype. There is evidence that the effects are both local and systemic.</p><p>Conclusion: Besides the mechanical effect of cupping increasing the local blood flow and stretching</p><p>local tissue, activation of the HO-1 system could account for many of cupping therapy’s claimed local</p><p>and systemic benefits.</p><p>Key Words: Cupping Therapy, negative pressure, heme oxygenase-1, ecchymosis, bilirubin, carbon</p><p>monoxide</p><p>Introduction</p><p>At the 2016 Summer Olympics, U.S. Athletes in swimming, gymnastics and track and field sports</p><p>competed with multiple circular marks on their backs and shoulders. These marks were produced by a</p><p>therapy known as “Cupping”. In interviews, these athletes claimed that this therapy provided effective</p><p>relief from the muscle and joint soreness that is associated with their respective sports and speedier</p><p>recovery from injuries. This has led to increased awareness and curiosity about of this therapy. It has</p><p>also provoked questions concerning the authenticity of this therapy and the claims that are made</p><p>concerning the benefits.</p><p>Cupping Therapy</p><p>Cupping therapy is an ancient traditional therapy that has been used throughout the world for</p><p>thousands of years.1 The oldest mention of this treatment is in an ancient Egyptian papyrus. It is a</p><p>technique found in many traditional Asian medicinal systems.2 It was promoted by ancient physicians,</p><p>such as Hippocrates, for a variety of conditions.3 Various forms of cupping were used in western</p><p>medicine until the early 1900’s. In the early twentieth century, August Bier, who developed procedures</p><p>that are still used in anesthesiology today, was a proponent of cupping in his “Passive Hyperemia</p><p>Therapy.”4,5,6</p><p>Cupping therapy, employed by various folk medicine providers, is a traditional treatment that may be</p><p>dismissed as ineffective or even harmful because of some of the visually unpleasant marks this therapy</p><p>leaves on patients and the unconventional explanations presented for this therapy’s mechanism of</p><p>action.7 Skepticism of cupping therapy, as well as the proposed mechanisms, can be found as far back as</p><p>1835 when Charles Alexandre Louis wrote, “and how then can we believe that the effect of a blister is to</p><p>check an inflammation, when this blister is one inflammation superadded to another?”8 With the</p><p>advent of antibiotics and other modern therapies, cupping fell out of fashion with western medicine, but</p><p>has continued to be popular by traditional practitioners throughout the world.</p><p>Techniques</p><p>There are several methods of traditional cupping.9 Wet cupping involves piercing the skin with needles</p><p>or small blades before applying the cups. Because it involves piercing the skin and removal of body</p><p>fluids, the physiological response to wet cupping would be expected to be different than its “dry”</p><p>counterpart, and is not evaluated in this paper. Moving cupping is a technique in which a lubricant is</p><p>used and after the cups are applied, they are slid along the skin.10 This does not normally lead to the</p><p>hallmark ecchymosis of the underlying skin that is the goal in stationary cupping. Dry Cupping involves</p><p>the application of a hollow container on the skin with suction. The suction is traditionally created by</p><p>placing a flame within the cup for a few seconds to heat the air, then removing the flame, and quickly</p><p>applying the opening of the cup to the skin. Skin is drawn up into the container due to the negative</p><p>pressure that is created as the air cools. Glass cups are used for the technique where fire is employed to</p><p>create the suction, though other materials have been used as by traditional cultures such as brass,</p><p>bamboo, and animal horn.2 Today the suction can be applied with hand pumps and electric pumps or</p><p>even with soft silicon cups the suction can be applied by hand.2,11</p><p>Traditional Indications</p><p>Though dry cupping in modern times is most often used for conditions involving pain, such as back pain</p><p>or arthritis, it has been traditionally recommended for systemic inflammatory conditions and to address</p><p>organs of the body far removed from the area of application.1,12,13 In ancient writings there was almost</p><p>no condition for which cupping was not considered appropriate treatment.14 Sandler and Haynes point</p><p>out that the 1923 edition of Abt’s Pediatrics lists indications for dry cupping in its chapter on</p><p>Therapeutic Technique as “acute congestion of pneumonias, bronchitis, or pulmonary edema with</p><p>marked dyspnea and cyanosis . . . mastoid disease and nephritis.”15,16</p><p>Traditional Explanations</p><p>The traditional explanations given of how cupping benefits a patient’s health vary significantly.</p><p>Anciently, the concept of removing “evil spirits” was a common theme. From Hippocrates time and</p><p>even until the late 1800’s, the redistribution and balance of the four cardinal “humors” was the</p><p>explanation being promoted by western physicians.14 In the early 20th century, it was proposed that</p><p>cupping stimulated the production of antitoxins within the tissue.17 Traditional Asian medicine describes</p><p>the benefits of cupping via the movement of “Qi” (pronounced “chee”) energy between 12 basic</p><p>meridians throughout the body.2 Even with such vague explanations of how it works, the significant</p><p>worldwide use by multiple cultures for over 3 thousand years would suggest that this therapy may elicit</p><p>a beneficial effect on human physiology. There has been some clinical research on the benefits of</p><p>cupping for various health conditions.9,12 While there is some evidence for efficacy, higher quality</p><p>studies still need to be done to</p><p>objectively evaluate clinical benefit.</p><p>Superficial Suction in Healthcare</p><p>Doctors in the 19th century used suction to produce hyperemia to improve healing.6 Suction has also</p><p>been used as a mechanism for studying capillary fragility in patients.6,18,19,20 Negative pressure is still</p><p>commonly used in modern medicine for more effective wound care and healing.21 Each medical use of</p><p>suction is based on the specific physiologic response to the negative pressure.</p><p>The concept of dry cupping is simple; locally applied negative pressure is applied over an area of skin. It</p><p>is retained from 5 to 10 minutes, or more, eliciting an area of petechiae, purpura or ecchymosis.22 The</p><p>ecchymosis resolves the same way a bruise would over approximately 7-14 days, with the colors slowly</p><p>changing over time. There has been research showing the physiological sequelae of negative pressure</p><p>on skin and the body’s reaction to blood external to its vascular containment in living tissues. Based on</p><p>this research, it might be possible to evaluate the physical and biochemical changes that would be</p><p>expected from dry cupping therapy.</p><p>The Effects of Localized Negative Pressure on Skin</p><p>When the cup is applied, centrally localized negative pressure produces compression of the skin at the</p><p>rim of the cup and distraction of the skin and underlying tissue within the interior of the cup. The depth</p><p>of distraction of the skin, underlying fat and muscle is dependent on the amount of negative pressure</p><p>employed and the diameter of the cup that is used.22 The lowered pressure within the interior of the</p><p>device causes a pressure differential between the skin surface and underlying blood vessels, eliciting an</p><p>almost immediate visible vasodilation of the superficial capillaries producing a localized hyperemia. In</p><p>one study there was a five-fold increase in vascular perfusion within the area of vacuum. Wider</p><p>diameter cups or greater suction was associated with increasing perfusion.23 Increased blood flow in the</p><p>patients muscles may be one of the mechanism cupping affects localized pain symptoms.24</p><p>Over time the increased vascular pressure in the vessels can cause rupture of capillaries with resultant</p><p>petechiae, purpura or ecchymosis developing within the area of the cup. Cutter in 1935 hypothesized</p><p>that some of the differences in appearance of the marks in individual patients may be due to variations</p><p>in capillary rupture versus capillary leakage by diapedesis, but there is no follow up research to</p><p>determine if this was ever verified.19</p><p>The result of the prolonged suction is extravascular blood within the subcutaneous tissue which is</p><p>similar to a bruise, but without the accompanying non-vascular tissue damage due to trauma.25 In 1924</p><p>Valmyre claimed that the depth of the ecchymosis from cupping was from 1 to 4 centimeters.26 In his</p><p>follow up letter in the British Medical Journal he states that this had been determined by autopsies on</p><p>patients who had cupping performed prior to their death. 27</p><p>As mentioned previously, like bruises, the resultant ecchymosis from cupping therapy resolves slowly</p><p>over many days. Insight into the physiological cascade that is stimulated by the presence of superficial</p><p>extravascular blood in bruises may illuminate possible influences of cupping therapy.</p><p>The Healing Bruise</p><p>The human body removes hemoglobin from the tissue by macrophages and the production of the</p><p>inducible enzyme heme oxygenase-1 (HO-1) which was identified in the 1960’s.28 This enzyme catalyzes</p><p>the hemoglobin heme into biliverdin(BV), carbon monoxide (CO) and iron. The BV is further reduced to</p><p>bilirubin (BR) by biliverdin reductase.</p><p>The initial dark color of a bruise is caused by the release of erythrocytes into the extravascular tissue.</p><p>Extravasation of blood into the tissue elicits an inflammatory reaction.29 Within 3-6 hours, neutrophils</p><p>are the first reactant cells to arrive in the area, but neutrophils, for the most part do not contain nor</p><p>produce HO-1.31 Background expression of HO-1, and the weaker constitutive form heme oxygenase-2,</p><p>is found in only small amounts within the dermal and subdermal tissues.30 At approximately 6 hours,</p><p>there is an increase in HO-1 concentration which is directly correlated to the arrival and increasing</p><p>concentration of macrophages.</p><p>The levels of HO-1 peaks in 1-3 days, then slowly starts to diminish. HO-1 levels are still increased above</p><p>basal levels even 7 days after initiation of the bruise.30 BV from heme gives a bruise a greenish color and</p><p>the conversion of BV to BR is the source for the yellow color in a bruise as it ages.31 The free iron, which</p><p>is highly reactive, is controlled by being rapidly bound by ferritin which is found in most tissues and</p><p>increased in the presence of heme.32</p><p>Heme Oxygenase-1 System</p><p>Activation of the HO-1enzyme system has been shown to have potent antioxidant, anti-inflammatory,</p><p>anti-apoptotic, anti-proliferative, and immunomodulatory effects throughout the body either directly or</p><p>via the biological activity of its products.33,34,35 HO-1 is a stress protein that responds to adverse</p><p>environmental conditions and directly contributes toward preventing or limiting tissue damage. The</p><p>increased synthesis of HO-1 protein is stimulated by a broad number of chemical and physical agents</p><p>beyond heme, such as inflammation, reactive oxygen and nitrogen species, cytotoxic chemicals, and</p><p>hypoxia. 36</p><p>HO-1 increases production of IL-10, an anti-inflammatory cytokine that stimulates resolution of</p><p>inflammation.37 In an autocrine fashion HO-1production is upregulated by increased levels of IL-</p><p>10.38,39,40 While HO-1increases IL-10, it simultaneously down regulates the production of pro-</p><p>inflammatory cytokines such as tumor necrosis factor (TNF) alpha and interleukin-6 (IL-6) and inhibits</p><p>the effects IL-1b.41,42,43 Antioxidant enzymes such as Catalase and Superoxide Dismutase are</p><p>significantly increased by the activity of HO-1.44,45,46</p><p>Besides the anti-inflammatory and antioxidant mechanisms, HO-1 increases tissue levels of vascular</p><p>endothelial growth factor (VEGF) and simultaneously stimulates mitochondrial biogenesis.53,47,48,49 All of</p><p>these effects would have significant benefit in wound healing. Consistent with this, increased HO-1</p><p>activity has been found to be a necessary factor in the healing of wounds. Stimulating this enzyme</p><p>accelerates healing, while inhibiting the enzyme delays the process.</p><p>50,51,52,53</p><p>In 1978 Myer found that pre-</p><p>treatment of a wound site with autogenous injections of blood elicited significantly stronger wound</p><p>tensile strength.54 He hypothesized that this was due to the stimulation of inflammation by the blood.</p><p>However, they found that the optimum timing between injection and wounding to maximize the effect</p><p>was 2 days. This would closely approximate the time when HO-1 was at maximum concentration and</p><p>activity, suggesting that the HO-1 system was a more likely candidate improving the healing. Evidence</p><p>of a systemic effect of HO-1 system activation is shown by improved wound healing in mice by</p><p>intraperitoneal injection of hemin, the ferric protoporphyrin-IX group from hemoglobin used to</p><p>stimulate HO-1 production.55</p><p>Products of HO-1: Biliverdin/Bilirubin</p><p>While toxic in higher concentrations, both BV and BR have been ascribed potent antioxidant affects</p><p>against both reactive oxygen and nitrogen species.56,57 Mildly elevated levels of bilirubin have been</p><p>shown to be associated with significant prevention of conditions such as atherosclerosis, diabetes and</p><p>cancer.58,59,60,61,62 Besides the antioxidant effect of BV/BR, elevated levels are also correlated with lower</p><p>levels of systemic inflammation as well.63,64 In mice and rats injections of BV or BR has significant anti-</p><p>inflammatory effects.65,66 BR has also been found to be and effective stimulator of wound healing in a</p><p>model of diabetes.67</p><p>Products of HO-1: Carbon Monoxide</p><p>Like its cousin, nitric oxide (NO), CO in the environment and at higher concentrations it is considered a</p><p>pollutant. CO has about 200 times the affinity for hemoglobin than oxygen. By strongly binding</p><p>hemoglobin, and forming carboxyhemoglobin, CO can lead to tissue hypoxia and eventually death.</p><p>While it is true that CO is toxic in higher amounts, this product of HO-1 activity in small amounts has</p><p>been shown to have anti-inflammatory, antiapoptotic, and antiproliferative activity, as well as being a</p><p>vasodilator and neuromodulator which includes anti-nociception.36,68</p><p>CO stimulates the production of cyclic guanosine monophosphate (cGMP) that leads to the vasodilation</p><p>of blood vessels, though the effect is slightly weaker than NO. CO inhibits inflammation by down</p><p>regulating inflammatory cytokines, such as IL-1b and tnf-alpha.69,70 CO inhibits depolarization of</p><p>nociceptors, possibly via activation of ATP-sensitive K+ channels, inhibiting pain.71</p><p>The physiologic effects of CO depend significantly on the concentration and the specific tissue</p><p>involved.72 The minute amounts generated by the normal physiology of the human body may not elicit</p><p>these biological functions in an appreciable amount, but with a larger pool of substrate, such as in a</p><p>bruise or produced by cupping, the increase in CO concentration due to HO-1 activation may be high</p><p>enough to stimulate the physiologic effects, without toxic levels.</p><p>The Local Effect</p><p>The immediate direct effects of suction on the area would increase local blood flow and lymphatic</p><p>flow.24,73 Local increase in blood flow and lymphatic flow would be beneficial for local myofascial pain.74</p><p>Considering the effects of activating the HO/BR/CO system, it could be presumed that the localized</p><p>result of the ecchymosis from cupping therapy would have anti-inflammatory, anti-oxidant and anti-</p><p>nociceptive effect in the local tissue, resulting in an eventual decrease in any local inflammation, and an</p><p>increase in angiogenesis and mitochondrial biogenesis as well as a decrease in local pain. This could lead</p><p>to shorter healing times for sprains, strains, or wounds depending on the locale and timing of the</p><p>cupping. This may be the mechanism behind a diminished perception of pain, which has been seen in</p><p>clinical research of cupping therapy’s effects on musculoskeletal pain.75,76</p><p>An injection of autologous blood into areas of tendon pain is a therapy for various tendinopathies, such</p><p>as lateral epicondylitis, used in sports medicine.77,78 In a similar way, the localized effects of cupping</p><p>therapy could be considered a non-invasive perfusion of the tissue with autologous blood.</p><p>The Systemic Effect</p><p>Cupping is claimed to have a systemic influence on the body, not just a localized benefit. Evidence of</p><p>systemic influence, far removed from the local biochemical tissue reaction is described in a 1953 Ohio</p><p>University study by Hamdy et al on the healing of bruises in animals.79 In their studies they found that</p><p>the rate of the appearance of bilirubin in a bruise and the time to heal of standardized bruises in</p><p>different species of animals, such as cattle, hogs, sheep and rabbits, was approximately the same</p><p>regardless of the species studied. In their third published article on bruised tissue they note that</p><p>whenever a previously bruised animal later received a second bruise, the second bruise would heal</p><p>faster than the initial bruise. In testing this phenomenon they inflicted standardized bruises on 120</p><p>rabbits. 3 days later they inflicted a second standardized bruise in 80 of the animals. 2 days after this</p><p>they elicited a third bruise in 40 of those rabbits that already had 2 bruises. They measured the time for</p><p>the appearance of BR and the time of visual disappearance of the bruise. The following was the result:</p><p>Mean Time for appearance MeanHealing Time</p><p>of bilirubin (hours) (Days)</p><p>First bruise 70 7.9</p><p>Second bruise 56 5.6</p><p>Third bruise 46 4.9</p><p>There was an earlier appearance of BR and a shorter healing time in the second bruises, and even</p><p>shorter times observed in the third bruise. This suggests that whatever process was stimulated to</p><p>initiate the catabolism of hemoglobin in the first bruise elicits more efficient resolution of the</p><p>subsequent bruises. It also would suggest that the larger the initial source of the “healing factor” (more</p><p>bruises), the larger the impact on subsequent bruises.</p><p>With these results in mind, they elected to evaluate whether this “healing factor” could be passively</p><p>transferred from one animal to another. They bruised a group of rabbits. 5 days later they transfused</p><p>20 ml of blood with 3ml of anticoagulant from the bruised rabbits into 5 other rabbits. They also had</p><p>control rabbits (no treatment), some rabbits they transfused with 20ml blood from non-bruised rabbits</p><p>plus 3ml of anticoagulant, and a few animals that they injected with 3ml of anticoagulant. 24 hours</p><p>after these infusions, they inflicted a standardized bruise in all of the animals. Again, they measured the</p><p>appearance of bilirubin and the mean healing time. The synopsis of their results is as follows:</p><p>Number of Source of Mean Time for appearance MeanHealing</p><p>Rabbits Infusion of bilirubin (hours) Time (Days)</p><p>5 Bruised Rabbits 43 6.1</p><p>14 Control (none) 70 7.9</p><p>4 Non-Bruised Rabbits 72 7.8</p><p>3 Only Anticoagulant 71 8.0</p><p>This would suggest that a bruise stimulates not only a localized chemical breakdown of hemoglobin in</p><p>response to blood within the tissue, but that these factors are increased within the general circulation as</p><p>well.</p><p>In animal models, injections of hemin are often used to stimulate HO-1 system activation. While</p><p>intraperitoneal injection is a more common method to stimulate systemic HO-1 production,</p><p>subcutaneous injections of hemin have been used successfully to stimulate the HO-1 system for</p><p>inflammatory conditions within organs such as the kidney and lungs.80,81,82 An increase in systemic levels</p><p>of BV/BR or CO may stimulate some anti-inflammatory effects, but they would not have been expected</p><p>to increase the resolution of bruises since that requires degradation of hemoglobin. This would suggest</p><p>that there is either a direct increase in concentration of circulating HO-1, or possibly an increase in the</p><p>circulation of the macrophages that have been primed to increase production of HO-1.</p><p>HO-1 and Macrophage Phenotype</p><p>Macrophage activation can be broadly divided into two phenotypes, M1 and M2, which can be further</p><p>subclassified. M1 macrophages express high levels of pro-inflammatory cytokines, high production of</p><p>reactive oxygen and nitrogen species, have anti-microbial activity and reflect a Th1 helper T-cell</p><p>response.83 M2 macrophages produce substances that promote resolution of inflammation and cell</p><p>proliferation manifesting a Th2 response. HO-1 stimulates the shift of macrophages to the M2</p><p>phenotypes.84,85,86,87 This includes subtypes of M2 macrophages that overexpress HO-1. For example, a</p><p>study in mice used intraperitoneal injections of hemin to stimulate HO-1 induction. This stimulated</p><p>increased levels of M2 macrophages that overexpress HO-1. These mice were fed a choline deficient diet</p><p>that induces pancreatitis. In the group injected with hemin there were no deaths due to induced</p><p>pancreatitis, whereas 7 of 16 of the control mice died.88</p><p>Higher levels of M2 macrophages that already overexpress HO-1, with production anti-inflammatory</p><p>substances such as IL-10, which also stimulates shift to M2 phenotype, may be part of the reason that</p><p>the “healing factor” was transferrable in Hamdy’s experiments on bruises. It may also be a significant</p><p>reason why cupping therapy has a systemic influence on conditions that are hallmarked by</p><p>inflammation.</p><p>More recently a study was performed</p><p>exposing mice to influenza virus and injected with hemin to</p><p>stimulate HO-1 production.89 The hemin elicited significantly less lung damage and 50% of the mice</p><p>survived verses none of the mice without the hemin injection. These author’s in vitro results also</p><p>showed HO-1 inhibited viral replication, though this was not seen in vivo. There have been other studies</p><p>that suggest HO-1 has antiviral activities against some important human pathogens.90 These studies</p><p>would support the effects of stimulation of the HO-1 system being beneficial in patients with illnesses,</p><p>such as flu and pneumonia, which is consistent with traditional indications for the use of cupping</p><p>therapy.</p><p>Similar Therapies; Stimulate Same Physiologic Cascade; Similar Results</p><p>Gua Sha is a traditional technique where lubricated skin is repetitively rubbed with a smooth edged</p><p>instrument which breaks superficial capillaries.91 This causes large areas of petechiae and ecchymosis .</p><p>The result is the same as dry cupping; blood in the extravascular space. This elicits the same stimulation</p><p>of the HO-1 system as cupping therapy as evidenced by the slow color change as the marks resolve. A</p><p>2009 study by Kwong, et al at Harvard Medical School showed that Gua Sha applied to the backs of</p><p>transgenic mice elicited a significant upregulation of HO-1, not just in the skin, but in organs of the</p><p>gastrointestinal tract, the genital tract, the liver, kidneys and others.92 In this study levels of HO-1</p><p>peaked at 36 hours, and were still increased above the baseline even 120 hours later. Like dry cupping,</p><p>this therapy has also been claimed to be effective for systemic inflammatory conditions.</p><p>Autohemotherapy, is another unconventional medical therapy in which venous blood is withdrawn and</p><p>then injected into the tissues of the same patient.93 This would also elicit the reaction of macrophages</p><p>and the production of HO-1, BV/BR, and CO very similar to the injection of hemin. While there are few</p><p>studies on Autohemotherapy, there are a few published reports of successful treatment of conditions</p><p>such as Herpes Zoster and chronic urticaria.94,95,96</p><p>The application of each of these therapies is significantly different, but the result is the same. Cupping</p><p>therapy, Gua Sha and Autohemotherapy all lead to endogenous extravascular blood, and would</p><p>stimulate the same physiologic reaction; attraction of macrophages and the stimulation of the HO-1</p><p>system with resulting anti-inflammatory/antioxidant products and shift to M2 macrophages. It is not</p><p>surprising that the beneficial health effects claimed for Cupping, Gua Sha, and Autohemotherapy are</p><p>very similar.</p><p>Pharmacological Aspects of Cupping Therapy and Some Unanswered Questions</p><p>While both heme and lysed erythrocytes both have been shown to stimulate HO-1 production/activity,</p><p>erythrocytes are metabolized about 10 times slower than free hemoglobin.97 This is consistent with HO-</p><p>1 activity peaking in 1-3 days and being sustained over a week’s time. Hemin, which has been used</p><p>effectively to study the benefits of HO-1 activation, has a short half-life of only a few hours. It is possible</p><p>that the extended activity of this enzyme system caused by erythrocytes may be advantageous by</p><p>prolonging the therapeutic effects of the HO-1 system over many days.</p><p>Summary</p><p>The following are well supported and accepted statements supported by the current literature:</p><p>1. Negative pressure on skin can elicit ecchymosis.</p><p>2. Ecchymosis attracts macrophages which phagocytize the erythrocytes and stimulates them to</p><p>produce HO-1 to metabolize the heme they contain.</p><p>3. HO-1 breaks down heme into BV/BR, CO and iron. The iron is sequestered by ferritin</p><p>4. HO-1, BV/BR, CO, directly and indirectly have significant antioxidant, anti-inflammatory, anti-</p><p>proliferative, and neuromodulatory activities.</p><p>5. HO-1 system activation can have both local and systemic effects.</p><p>Scientists are researching ways to activate and modulate the HO-1 system to address conditions such as</p><p>cardiovascular disease, kidney disease, asthma, sepsis, lung injury and other inflammatory diseases and</p><p>conditions.98,99,100,101</p><p>They are attempting to use both natural and pharmacological substances to</p><p>stimulate these endogenous anti-inflammatory, anti-oxidant and anti-proliferative substances to benefit</p><p>human health.102,103,104,105,106</p><p>Cupping therapy activating the HO-1 enzyme system is visibly demonstrated in cupping patients by the</p><p>slow changing colors and resolution of the ecchymosis. It is reasonable to assume that the larger the</p><p>surface area involved, the more macrophages would be attracted to the area and the larger the</p><p>activation of the HO-1 system and higher concentration of resultant CO/BV/BR as well as M2</p><p>macrophages. Would a larger involved surface area improve the effect of the cupping? A set of eight</p><p>7cm diameter cups would elicit 8 ecchymotic marks on a patient, with a total surface area of</p><p>approximately 307cm2. Would that have a different effect than 4 or 6 cupping marks at 153cm2 or</p><p>230cm2? Because of the delay of production of HO-1, would cupping every other day for three</p><p>treatments be more effective for some illnesses than one treatment with more cups?</p><p>Cupping therapy has evidently been endogenously stimulating the activity of the HO-1 system for</p><p>thousands of years. So it is not a question as to “if” HO-1 is upregulated, but is there enough activation</p><p>of the HO-1 system in these patients to stimulate the local or systemic health benefits claimed for this</p><p>therapy?</p><p>Acknowledgements: I would like to thank Diane Flynn, M.D., Tyler Snow, D.P.T., Michael Clay, D.C., and</p><p>Aaron Harris, D.C. for their invaluable input and suggested edits.</p><p>The views expressed are those of the author(s) and do not reflect the official policy of the Department</p><p>of the Army, the Department of Defense or the U.S. Government.</p><p>1 Rozenfeld E, Kalichman L. New is the well-forgotten old: The use of dry cupping in musculoskeletal</p><p>medicine. J Bodyw Mov Ther. 2016 Jan;20(1):173-8.</p><p>2 Mehta P, Dhapte V. Cupping therapy: A prudent remedy for a plethora of medical ailments. J Tradit</p><p>Complement Med. 2015 Feb 10;5(3):127-34.</p><p>3 Christopoulou-Aletra H, Papavramidou N. 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