Some Inflammatory Remarks About Manipulation

By Anthony Rosner, PhD, LLD [Hon.], LLC

There is an anonymous quote which reads, "An archer cannot hit the bullseye if he doesn't know where the target is." In the case of some of chiropractic's detractors, that seems to have been the case when it comes to vertebral arteries.

For while such critics may have appeared to have singled out the vertebral artery as an element of the circulatory system prone to destruction at the hands of a chiropractor and leading to stroke,^1-3they and too many others fail to recognize another, more widespread element in the entire circulatory system.

That element is inflammation in the chronic state. As an acute reaction, inflammation represents the proactive biological response of vascular tissue to harmful stimuli, such as pathogens, damaged cells, or irritants. Without it, wounds would never heal and infections would never clear. However, in thechronic state, a host of intermediates have been identified [VCAM-1 (adhesion molecule), cytokines (tumor necrosis factor α, interleukin-6, interleukin-18), proteases (metalloproteinase, MMP-9), platelet products (CD40L), myeloid-related protein (MRP 8/14), adipokines (adiponectin), and acute-phase reactants (C-reactive protein, plasminogen activator-1, fibrinogen)].^4-5

Chronic inflammation is implicated in a wide range of disorders ranging from hay fever to periodontitis, rheumatoid arthritis,⁶ and especially atherosclerosis (which is the focus of this article). Ironically, there is more evidence to support the hypothesis that spinal manipulationpreserves arterial integrity rather than degrading it.

In their exhaustive review of plaque and ultimately thrombus formation in the arteries, Packard and Libby describe how chemotactic cytokines (called chemokines) direct a number of processes on the way to plaque and thrombus formation:^4-5

• By providing a chemotactic stimulus, chemokines direct migration of circulating leukocytes, which have adhered to the outer arterial wall, into the intima. There, the leukocytes take residence and divide.
• The leukocytes secrete pro-inflammatory cytokines and drive the progression of the lesion.
• Additional cytokines and growth factors are secreted, which promote growth and migration of smooth muscle cells (SMCs).
• In response to inflammatory stimulation, vascular SMCs secrete enzymes that can degrade elastin and collagen, which allow their penetration into the expanding lesion.
• The fibrous cap of the plaque, with diminishing collagen, weakens.
• When the fibrous cap ruptures, tissue factor triggers formation of a thrombus.
• Clinically, this may translate into an acute coronary syndrome.

What does all this mean? In the words of Packard and Libby, "inflammation participates pivotally in all stages of atherosclerosis, from lesion initiation to progression and destabilization." But more importantly, they state that "the example of inflammation in atherosclerosis illustrates rapid translation of basic science understanding to the clinic."⁴

How does this relate to spinal manipulation? Consider basic animal studies from the laboratory of Xue-Jun Song at the Parker College of Chiropractic and human studies as conducted by Julita Teodorczyk-Injeyan and Stephen Injeyan at the Canadian Memorial Chiropractic College.

Song pointed out that numerous indicators of inflammation (thermal and mechanical hyperalgesia, excitability of sensory neurons as shown by electrophysiological measurements, and increased vascularization and surrounding of the dorsal root ganglia cells by glia cells) all showed that the inflammatory process produced by the injection of an inflammatory cocktail could be reversed by the application of adjustments (instrument-assisted) to the L5 or L5+L6 spinous processes of rats. The effect was segmental, as application to the L4 segment failed to reverse the indicators of inflammation.⁷

Turning to humans, Teodorczyk-Injeyan and Injeyan demonstrated that cavitation-producing Carver-Bridge spinal manipulations in asymptomatic subjects displayed a gradual reduction of two pro-inflammatory cytokines: tumor necrosis factor α and interleukin-1β as seen in tissue culture. The conclusion was that subjects undergoing a spinal manipulation displayed a time-dependent attenuation of inflammatory cytokines; meaning that spinal manipulation could have produced a down-regulation of inflammatory-type responses via a central, unknown mechanism.⁸ This work was later extended to include the reduction of another pro-inflammatory cytokine (interleukin-6) after spinal manipulation.⁹

Carrying these observations into symptomatic patients, the CMCC investigative team posed the following hypothesis: Is the production of inflammatory mediators and chemotactic cytokines (chemokines) altered in patients with chronic/recurrent neck pain? By collecting blood and serum samples from 27 neck pain patients and 13 asymptomatic controls, Teodorczyk-Injeyan and Injeyan demonstrated that the chemotactic cytokine tumor necrosis factor α, the monocyte chemotactic protein 1 (CCL2/MCP-1) as well as serum nitric oxide, were elevated in the neck pain patients, but not in the asymptomatic controls.¹⁰ The role of nitric oxide is significant because inflammatory and chemotactic cytokines are strong inducers of nitric oxide production; with nitric oxide playing a role in the mediation of peripheral and chronic nociception, including spinal pain.^11,12

What remains to be seen is whether spinal manipulation in symptomatic humans brings about both the reduction of pain and the levels of key pro-inflammatory intermediates for clinically meaningful periods of time. First to be examined would be the cytokines: tumor necrosis factor α, interleukin-1β, and interleukin-6. But it is also very tempting to examine the levels of homocysteine, found to have a multiplicity of inflammatory and other deleterious effects on health.¹³

In this manner, there is the potential to come full circle in demonstrating not only that the benefits of spinal manipulation outweigh the risks, but that these benefits extend to the integrity of the artery itself. To paraphrase General Eisenhower's remarks in planning his response to the German invasion during the Battle of the Bulge in 1944-1945, there is the potential here to turn a potential defeat into a stunning victory.

References

1. Ernst E, Assendelft WJ. Chiropractic for low back pain: We don't know whether it does more good than harm. (Editorial) British Medical Journal, 1998;317(7152]):160.
2. Reuter U, Hamling M, Kavuk I, Einhaupl EK, Schielke E, for the German vertebral artery dissection study group. Vertebral artery dissections after chiropractic neck manipulation in Germany over three years. Journal of Neurology, 2006;253:724-730.
3. Albuquerque FC, Hu YC, Dashti SR, Ablas AA, Clark JC, Akire B, Theodore N, McDougall CG. Craniocervical arterial dissections as sequelae of chiropractic manipulation: patterns of injury and management. Journal of Neurosurgery, 2011. doi:10.3171/2011.8.JNS.11212.
4. Packard RS, Libby P. Inflammation in atherosclerosis: From vascular biology to biomarker discovery and risk prediction. Clinical Chemistry, 2008;54(1):24-38.
5. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation, 2002;105:1135-1143.
6. Majithia V, Geraci BA. Rheumatoid arthritis: diagnosis and management. American Journal of Medicine, 2007;120(11):936-939.
7. Song XJ, Gan Q, Cao J-L, Wang Z-B, Rupert RL. Spinal manipulation reduces pain and hyperalgesia after lumbar intervertebral foramen inflammation in the rat. Journal of Manipulative and Physiological Therapeutics, 2006;29(1):5-13.
8. Teodorczyk-Injeyan JA, Injeyan HS, Ruegg R. Spinal manipulative therapy reduces inflammatory cytokines but not substance P production in normal subjects. Journal of Manipulative and Physiological Therapeutics, 2006;29(1):14-21.
9. Teodorscyzk-Injeyan J, Injeyan HS, Ruegg R. Spinal manipulative therapy (SMT) augments production of anti-inflammatory cytokine IL-10 in normal subjects. Proceedings of the 9th Biennial Congress of the World Federation of Chiropractic, Vilamoura, Portugal, May 17-19, 2007:143-144.
10. Teodorczyk-Injeyan JA, Triano JJ, McGregor M, Woodhouse L, Injeyan SH. Elevated production of inflammatory mediators including noceptive chemokines in patients with neck pain: a cross-sectional evaluation. Journal of Manipulative and Physiological Therapeutics, 2011;34(8):498-505.
11. Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, et al. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients.Inflammation Research, 2007;56:32-37.
12. Bogdan C. Nitric oxide and the immune response. Nature Immunology, 2001;2:907-916.
13. Rosner A. Spontaneous cervical artery dissections: another perspective. Journal of Manipulative and Physiological Therapeutics, 2004;27(2):124-132.