International Journal of Osteopathic Medicine (2011) 15, 13e21

www.elsevier.com/ijos

REVIEW

Osteopathic lymphatic pump techniques to enhance immunity and treat pneumonia

Lisa M. Hodge a,b,*
a

Osteopathic Research Center, University of North Texas Health Science Center, Fort Worth, Texas, USA Department of Molecular Biology, University of North Texas Health Science Center, Fort Worth, Texas, USA

Received 22 July 2011; revised 17 October 2011; accepted 3 November 2011

KEYWORDS
Cytokines; Chemokines; Inammation; Gastrointestinal lymphoid tissue; Pneumonia; Infection; Lymphatic pump techniques; Lymphatic system; Osteopathic manipulative medicine; Immunity

Abstract Pneumonia is a common cause of morbidity and mortality worldwide. While antibiotics are generally effective for the treatment of infection, the emergence of resistant strains of bacteria threatens their success. The osteopathic medical profession has designed a set of manipulative techniques called lymphatic pump techniques (LPT), to enhance the ow of lymph through the lymphatic system. Clinically, LPT is used to treat infection and oedema and might be an effective adjuvant therapy in patients with pneumonia. The immune system uses the lymphatic and blood systems to survey to rid the body of pathogens; however, only recently have the effects of LPT on the lymphatic and immune systems been investigated. This short review highlights clinical and basic science research studies that support the use of LPT to enhance the lymphatic and immune systems and treat pneumonia, and discusses the potential mechanisms by which LPT benets patients with pneumonia. Published by Elsevier Ltd.

Introduction
Infectious diseases, such as pneumonia, are a common cause of morbidity and mortality worldwide. Antibiotics are generally effective for
* Corresponding author. Osteopathic Research Center, The University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. Tel.: 1 817 735 2119; fax: 1 817 735 2118. E-mail address: [email protected]. 1746-0689/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.ijosm.2011.11.004

the treatment of infection; however the continual emergence of antibiotic resist strains of bacteria threatens their effectiveness. The mammalian immune system has evolved to defend the body against infection. Immune cells continually recirculate from the bloodstream through the peripheral or secondary lymphoid organs, and then return to the bloodstream via the lymphatic vessels in a process termed immune surviellance.1,2 Innate immunity is the rst line of defense against infection and includes

14 complement proteins, granulocytes, mast cells, macrophages, dendritic cells, and natural killer (NK) cells. Adaptive immunity is mediated by antigen-specic B and T cells, which induce immunological memory. Together, these two components of the immune system act to survey the body for infection, propagate and activate immune cells, kill infectious organisms and mount immunological memory.1 Furthermore, during infection, pro-inammatory cytokines, chemokines, and reactive oxygen and nitrogen species are released from injured tissue to enter blood and lymph.2 Leukocytes utilize this inammatory tissue gradient to detect sites of infection and inammation in the body. Once recruited, these leukocytes can directly kill pathogens and continue to release inammatory mediators, propagating the chemo-attractive gradient and activating other cells of the immune system.2 As pathogens are cleared from tissue, the inammatory gradient subsides and the concentration of leukocytes and inammatory mediators decreases.1,2 The lymphatic system collects uid, immune cells, antigens, pathogens and proteins from the tissue interstitial space and delivers them to regional lymph nodes.2 Intrinsic physiological factors such as skeletal muscle contraction, intestinal motility, and respiratory motions facilitate the ow of lymph through lymphatic vessels.2,3,4,5 External forces such as exercise6,7 passive limb movement,8 and body-based manipulative medicine techniques6,7,9e12 have also been shown to increase lymph ow. If this circulation of lymph is restricted in any way, there could be a delay in the immune response to a pathogen, which could compromise the health of an individual.3,13 The osteopathic medical profession has designed a set of osteopathic manipulative techniques (OMT), called lymphatic pump techniques (LPT), to enhance the ow of lymph through the lymphatic system.13e15 Lymphatic pumps can be applied to the thoracic cage, abdomen (splenic and liver pumps), feet and legs (pedal pumps).13 Clinically, LPT is used to treat infection and eodema13,14 and might be an effective adjuvant therapy in patients with pneumonia.16e18 While there are few published clinical studies examining the effect of LPT on infection and immunity, recent studies in animals have shown that LPT enhances the uptake of lymph into the lymphatic system19 and increases lymph ow and leukocyte output.9,10,12 By enhancing the lymphatic release of immune cells, LPT may enhance immunemediated protection against infectious disease; however, further studies are required to conrm

L.M. Hodge this theory. A better understanding of these mechanisms should provide a scientic basis for the clinical use of LPT.

Lymphatic pump techniques enhance the lymphatic and immune systems

Early studies in humans suggest LPT may enhance innate immunity in both healthy individuals20,21 and patients with acute infectious disease22; however, it is important to note these were pilot studies with a limited numbers of subjects. More recently, Knott et al demonstrated that both thoracic and abdominal LPT increase thoracic duct lymph ow in dogs.6 Subsequently, Hodge et al found the application of LPT to the abdomen stimulates the release of immune cells from lymph nodes that directly enter lymphatic circulation.10 In this study LPT also increased lymph ow and the concentration of immune cells within the lymph of dogs.10 Table 1 illustrates the effect of four minutes of LPT on thoracic duct leukocyte ux (i.e. immune cells per minute of lymph collected) in anesthetized dogs. While the release of leukocytes into lymph during LPT was transient, four minutes of LPT produced a net increase of 6 x 108 leukocytes into thoracic duct lymphatic circulation, which included cells of both the innate and adaptive immune system. In addition, LPT had no preferential effect on any of these immune cells, since neutrophils, monocytes, total lymphocytes, CD4 T cells, CD8 T cells, and IgA and IgG B cell numbers were similarly increased. Similar results were seen in mesenteric lymph.10 Collectively, this data suggests application of LPT to the abdomen mobilizes immune cells from the mesentery into lymph circulation, which then delivers these cells to venous circulation. While enhanced lymph ow and leukocyte concentrations may explain some of the clinical benets of LPT, additional factors, such as inammatory cytokines, chemokines and reactive oxygen and nitrogen species also inuence immunity. Therefore, to determine if LPT would mobilize inammatory mediators into lymphatic circulation, thoracic or intestinal lymph of healthy dogs was collected at resting (Pre-LPT), during 4 min of LPT, and for 10 min following LPT (Post-LPT) and measured for the concentration of IL-2, IL-4, IL-6, IL-10, IFN-g, TNF-a, MCP-1, keratinocyte chemoattractant (KC), superoxide dismutase (SOD), and nitrotyrosine (NT).11 LPT signicantly enhanced the lymphatic ux of these inammatory mediators, which may enhance protection against infection by redistributing these mediators to

Osteopathic lymphatic pump techniques to enhance immunity and treat pneumonia

Table 1 Abdominal LPT increases leukocyte ux in thoracic duct lymph. Pre-LPT Neutrophils Monocytes Lymphocytes CD4 T cells CD8 T cells IgA B cells IgG B cells 0.27 0.12 0.34 0.14 10.32 4.53 3.25 0.62 1.24 0.37 0.65 0.18 1.06 0.21 LPT 3.67 0.96b 4.24 1.18a 81.1 22.2b 43.7 5.57b 16.3 4.12b 9.02 0.86b 13.4 4.81a Post-LPT

15

0.29 0.01 0.36 0.10 7.30 2.30 5.10 1.90 2.23 0.76 0.60 0.21 0.78 0.18

Data are means 106 immune cells/min SE from six experiments. a Greater than pre-LPT and post-LPT (P < 0.01) b Greater than pre-LPT and post-LPT (P < 0.001). Republished with kind permission from Lymphatic Research and Biology.

other tissues. In support of this, lymph has been shown to redistribute mesenteric-derived cytokines and chemokines to distant organs, activate leukocytes and increase endothelial cell permeability.23 Therefore, it is likely that LPT enhances this redistribution, which may enhance immune function. Further experimentation is required to dene this mechanism. Recently, the laboratory of LM Hodge developed a rat model to study the effects of LPT on the lymphatic and immune systems.12 In this study the cisterna chili of rats were cannulated and lymph was collected during four minutes of pre-LPT (baseline), four minutes of LPT, and 10 minutes post-LPT (recovery). LPT treatment was applied to the rat to simulate, as much as possible, how LPT is applied to the abdomen of humans. To perform LPT, the operator contacted the abdomen of the rat with the thumb on one side and index nger and middle nger on the other side of the medial sagittal plane. The ngers were placed bilaterally caudal to the ribs, and pressure was exerted medially and cranially to compress the abdomen until signicant resistance was met against the diaphragm, then the pressure was released. Compressions were administered at approximately one/second for the duration of the 4 min of treatment. Consistent with ndings in dogs,9,10 LPT transiently increased lymph ow and the concentration of lymphatic immune cells and increased the numbers of mesenteric derived lymphocytes into lymph.12 Immunologically mature cells are known to continuously recirculate in the peripheral blood, spleen, and lymphatic vessels. 1 Therefore, It is likely that by increasing the numbers of immune cells in lymphatic circulation, LPT boosts immune surveillance. In support, LPT increased the numbers of IgA and IgG B cells in both thoracic and mesenteric lymph,10 demonstrating that LPT released mature, activated lymphocytes

in lymph circulation. This may explain, in part, the protective effects of LPT observed in patients with pneumonia. However, it is currently unknown whether the functions of these LPT-mobilized immune cells are enhanced. It is important to note that the effect of thoracic LPT on lymphatic immune cells in dogs or rats has not been measured. This is primarily due to two technical difculties: (1) application of thoracic LPT to animals that have just undergone thoracic surgery; and (2) maintenance of lymph duct catheter ow in chronically instrumented animals. However, in 2005 a study was published in which ow transducers were inserted into the thoracic ducts of dogs, and lymph ow was measured during thoracic and abdominal LPT and exercise.6 All interventions increased thoracic duct ow, but the greatest increases were seen in animals that received abdominal LPT or exercise. While these investigators did not collect lymph for analysis of immune cell concentrations, thoracic LPT greatly enhanced thoracic lymph ow. In addition, thoracic LPT has been shown to enhance antibody responses in humans.24,25 Therefore, similar to abdominal LPT, thoracic LPT likely enhances the release of immune cells into lymphatic circulation; however further experimentation is required to clarify this point.

Lymphatic pump techniques for the treatment of pneumonia

Pneumonia is a common cause of morbidity and mortality worldwide. The wide use of vaccines and anti-microbial treatments have substantially reduced the rate of death from infectious disease; however, the prevalence of organisms resistant to vaccines and antimicrobial therapy have increased substantially in recent years, raising the possibility that these treatments will become less effective in

16 the future.26,27 Therefore, there is a growing need to investigate the effectiveness of alternative therapies for the treatment of infectious disease. LPT has been used as an adjunctive therapy to improve cleansing of the tracheobronchial tree, increase sputum production and shorten the duration of cough in patients with lower respiratory tract disease.16,17 Recently, the multi-center osteopathic study in the elderly (MOPSE) conducted a double-blinded randomized, controlled trial to measure the efcacy of osteopathic manipulation as an adjunctive treatment for hospitalized elderly patients with pneumonia.18 Within 24 h of admission, subjects were randomised into conventional care, conventional care plus light-touch, or conventional care and OMT. Conventional care consisted of treatment for pneumonia as directed by their attending physicians. OMT or light-touch treatments were applied to patients supine in bed twice daily (6 h apart) for 15 min and continued until hospital discharge, cessation of antibiotics, respiratory failure (ventilator dependent), death, or study withdrawal. OMT was applied in the following sequence: thoracolumbar soft tissue, rib raising, doming of the diaphragm myofascial release, cervical spine soft tissue, suboccipital decompression, thoracic inlet myofascial release, thoracic LPT with activation, and pedal LPT. Soft tissue techniques consisted of massage, stretching, kneading, and direct inhibitory pressure to relax the musculature. Non-thrust techniques were used to treat areas unaddressed by the above techniques and were limited to 5 min. The light touch treatment imitated the OMT protocol, generally touching the same areas treated with OMT for the same duration. Self reported side effects were mild (post-treatment musculoskeletal soreness or pain), but signicantly (P 0.003) higher in the OMT group. Primary clinical outcomes measured were the length of hospital stay, time of clinical stability and pneumonia-specic symptomatic and functional recovery scores. Secondary outcomes measured were the duration of oral and intravenous antibiotics, treatment endpoint (including respiratory failure or death), hospital readmission rate, daily body temperature, daily respiratory rate and white blood cell counts (WBC). A total of 406 subjects were utilized for the study. There were no signicant differences between groups on compliance with antibiotic treatment guidelines and clinical measures, which included comorbidities and pneumonia severity. Intention-to-treat analysis found no signicant difference between the groups for any outcome. However, per-protocol analysis found OMT plus

L.M. Hodge conventional care decreased in length of hospital stay, the duration of intravenous antibiotics respiratory failure or death compared to the conventional care group alone. This result suggests that OMT is protective against pneumonia if a patient received the protocol as prescribed, without missing any treatment. It is important to acknowledge that intention to treat analysis likely reects actual clinical conditions. Of interest, the authors also found that lighttouch outcomes generally fell between OMT and conventional care, but were not signicantly different from either, suggesting the therapeutic effects of OMT and light-touch overlap. In support, light touch in rats excites the nervous system.28 Furthermore, touch therapy has been used clinically for pain relief.29 These ndings suggest that light touch stimulates the nervous system, which may benet patients in pain. However, the clinical benets of light touch, if any, are not clearly dened. Enhancing the lymphatic release of leukocytes may explain, in part, how LPT improves clinical outcomes in patients with infectious disease, such as pneumonia. To determine if LPT would facilitate the clearance of pulmonary bacteria, the laboratory of LM Hodge applied LPT to rats using a pneumococcal pneumonia disease model.30 This study was approved by the Institutional Animal Care and Use Committee at the University of North Texas Health Science Centre and conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH Publication no. 85-23, revised 1996). Sixty male JVC Fischer 344 rats (Charles River Laboratories, Wilmington, MA) weighing 250e300 g, and free of clinically evident signs of disease were used for this study. Rats were fed a standard laboratory diet and allowed to eat and drink ad libitum. Rats were nasally infected with 1 108 Streptococcus pneumoniae (kindly provided by Dr. Jerry Simecka at the University of North Texas Health Science Center, Fort Worth, Texas) colony forming units (CFU) as previously described. 31 Twenty-four hours after infection, rats were divided into control (N 20), sham (N 20) or LPT (N-20) treatment groups. For seven consecutive days rats received either (1) A daily sham treatment consisting of intravenous administration of 10 mg/kg propofol anaesthesia followed by four minutes of light touch, (2) Four minutes of LPT daily under propofol anaesthesia or (3) No treatment or anaesthesia (control). The application of LPT to the rats was performed as previously described.12 Briey, anesthetized rats were kept in a right lateral recumbent position. To perform LPT,

Osteopathic lymphatic pump techniques to enhance immunity and treat pneumonia the operator (Kyle Gummelt, D.O.) contacted the abdomen of the rat with the thumb on one side and index nger and middle nger on the other side of the medial sagittal plane. The ngers were placed bilaterally caudal to the ribs. Sufcient pressure was exerted medially and cranially to compress the lower ribs until signicant resistance was met against the diaphragm, then the pressure was released. Compressions were administered at a rate of approximately one/second for the duration of the 4 min of treatment. During sham treatment, rats were anesthetized and the operator contacted the abdomen of the rat for four minutes in a manner similar to LPT; however no compressions were made. Eight days after infection, lungs were collected and measured for S. pneumoniae bacteria and the concentration of immune cells as previously described.12,31e33 Data from control, sham and LPT treatment rats were analyzed by analysis of variance (ANOVA) followed by a Tukey multiple comparisons post test using Graphpad Prism version 5.0 for Windows, (GraphPad Software, San Diego, CA). Differences among mean values with P  0.05 were considered statistically signicant. Data are presented as arithmetic means standard error (SE). Both LPT and sham treatment reduced bacteria in the lungs compared to control (Figure 1);

17

however, LPT cleared more bacteria compared to sham treatment. During the eight days of infection, control rats were unable to clear bacteria from their lungs at any time point. It is plausible that the propofol anaesthesia administered to both the LPT and sham treatment groups provided a protective effect during pneumonia. In support, propofol has been shown to protect against acute lung injury in rats by abrogating the microvascular leakage of water and protein in the lungs and suppressing oxidative and other inammatorymediated injuries.34,35 Also, light touch may have enhanced protection against pulmonary infection, though the mechanism is uncertain. Importantly, LPT signicantly (P < 0.01) reduced bacterial numbers compared to sham, suggesting LPT induces either a separate or additive protective mechanism compared to sham alone. It was not surprising that LPT and sham treatment rats had fewer immune cells in their lungs since infection was subsiding in these rats (Figure 2). Immune cells are known to trafc into the lung during inammation36 and leukocytes have been shown to quickly increase in blood and lung tissue in response to pneumococcal pneumonia37; therefore, It is possible that LPT may have increased the numbers of immune cells trafcking into the lungs at an earlier time (after just a few treatments), which was sufcient to

108

Streptococcus pneumoniae CFU/lung

107

106

105

**

104

Control

Sham

LPT

Treatment group

Figure 1 LPT reduces Streptococcus pneumoniae colony forming units during acute pneumonia. Rats were nasally infected with 1 108 Streptococcus pneumoniae colony forming units (CFU). At 8 days post-infection, lungs were collected and measured for the total number of S. pneumoniae bacteria in the lungs. Data are means SE. **P < 0.01 compared to control and sham. N 10 rats per group.

18 reduce bacterial numbers, thereby reducing immune cells within the lungs by 8 days postinfection. It is also likely that this protection is not solely immune cell mediated. For example, LPT may have enhanced the concentration of pulmonary antimicrobial products such as surfactant proteins, defensins, lysozyme and lactoferrin. In addition, LPT may have enhanced respiratory ciliary beat, cough reex, and mucus clearance. Future experimentation is required to identify the LPT-mediated protective mechanism(s) in this disease model. It is interesting that LPT offered the greatest protection and sham treatment offered intermediate protection against pneumonia in rats. This nding is consistent with the clinical outcomes seen in the MOPSE study and suggests that OMT, and in particular LPT, may enhance the clearance of bacteria in patients with pneumonia. It also suggests that light touch has a therapeutic effect. It is important to note that these animal studies focused specically on LPT, whereas the clinical trial utilized many osteopathic techniques, including LPT. There are also obvious differences between the application of LPT in humans and animals, which is an inherent aw in using animal models to study the mechanisms of human manual medicine treatments. Also, unlike humans, to apply LPT and light touch (sham treatment), rats were placed under anaesthesia, which may have
6x10 6

L.M. Hodge augmented host defences during infection. Nonetheless, this study demonstrates that the rat is a useful model to study the therapeutic effects of LPT. Also, animal models provide data that cannot be obtained from humans and may provide insight into the mechanisms by which LPT enhances the lymphatic and immune systems and protects against infectious disease.

Proposed mechanism by which lymphatic pump techniques protect against pneumonia

The innate immune response provides the rst line of defence against infection and involves macrophages, neutrophils, natural killer cells, innatelike lymphocytes, complement proteins, and inammatory mediators. Hodge et al. reported that LPT signicantly increased the ux of immune cells in thoracic and mesenteric lymph.11 Of importance, macrophages and neutrophils are cells of the innate immune response against infection.36,38 Specically, pulmonary infection activates macrophages, which then release proinammatory cytokines and chemokines that serve as chemo-attractants for neutrophils. Once recruited into the lungs, neutrophils can phagocytose and kill bacteria.31,32,36,37 Both neutrophils

Total Lung Leukocytes

4x10 6

*
2x10 6

**

Control

Sham

LPT

Treatment group
Figure 2 Pulmonary immune cell numbers in rats with acute pneumonia. Rats were nasally infected with 1 108 Streptococcus pneumoniae colony forming units (CFU). Eight post-infection, lungs were collected and measured for the total number of pulmonary immune cells. Data are means SE. *P < 0.05 compared to control. **P < 0.01 compared to control. N 10 rats per group.

Osteopathic lymphatic pump techniques to enhance immunity and treat pneumonia and macrophages can also exert anti-microbial actions by releasing reactive oxygen species (ROS) and reactive nitrogen species (RNS).38 Therefore, by enhancing the release of macrophages and neutrophils in circulation (see Table 1), LPT may enhance innate immunity to pathogens and thereby facilitate their clearance during acute pneumonia. In addition, LPT was shown to enhance the uptake of interstitial tissue antigen into the initial lymphatics.19 Within the lymph nodes, antigen specic lymphocytes are stimulated to proliferate and differentiate into effector cells, thus protecting the host during the current infection.1,2 Therefore, during infection, LPT may facilitate the delivery of tissue antigens to regional lymph nodes and thereby enhance the lymphocyte response to microbial antigens. A signicant number of lymphocytes will also differentiate into long-lived memory cells, which respond rapidly during subsequent exposure to the same pathogen. Targeting immunological memory is the goal of immunization, and in humans LPT has been shown to increase vaccine specic immunity.24,25 In animals, Hodge et al also found LPT increased the numbers of CD4 T cells, CD8 T cells and B cells. Specically, LPT increased IgA B cells and IgG B cells in the thoracic (see Table 1) and mesenteric lymph suggesting LPT is able to mobilize mature, isotype-switched memory lymphocytes into lymphatic circulation. Collectively, these reports suggest LPT enhances immunological memory, which may aid in the clearance of pathogens with a long incubation period or prevent the development of chronic infection. Furthermore, Hodge et al. identied the gastrointestinal lymphoid tissue (GALT) as a tissue that releases immune cells into lymphatic circulation during LPT.10,12 The gastrointestinal lymphoid tissue (GALT) is the largest immunological tissue,39,40 and therefore a major site of antigen induction. GALT includes the lamina propria, Peyers patches, and the mesenteric lymph nodes (MLN). Antigen specic gastrointestinal derived lymphocytes can redistribute to the lung and provide protection during pulmonary infection.41e44 Enhanced pulmonary trafcking of gastrointestinal immune cells may explain, in part, the clinical benets of administering LPT to patients with pneumonia. While studies show promise for the use of LPT to enhance the immune system not all studies examining the effect of LPT on the immune system had positive outcomes. For example, serum interferon (IFN) levels of healthy subjects were unchanged throughout a 24-h period

19

following LPT.45 However, serum IFN levels should not be elevated in healthy individuals, which was a limitation to this study. Furthermore, a recent clinical study reported that when OMT (which included LPT) was applied to patients with COPD, it mildly worsened pulmonary function measures immediately posttreatment when compared to pre-treatment.46 Despite this outcome, the patients subjectively reported they beneted from OMT. Finally, inuenza vaccination did not increase inuenzaspecic antibody titers in nursing home residents.47 Importantly, the authors reported a reduction in general antibiotic by these patients use during inuenza season.

Conclusions
The prevalence of organisms resistant to vaccines and antimicrobial therapy has increased substantially. Therefore, there is a need to examine the benets of alternative medicinal procedures for treatment and prevention of infectious disease. The osteopathic medical profession has long recognized the importance of the lymphatic system in maintaining health. Clinical studies support the notion that LPT is associated with increased blood leukocyte counts, increased antibody responses to bacterial antigens and immunization and with shorter durations of intravenous antibiotic therapy and hospital stay. However, many of these were pilot studies, nor have all positive clinical outcomes been associated with immunity following LPT. Recent animal studies support the hypothesis that LPT enhances the lymphatic and immune systems and protects against pneumonia. While reasonable explanations for enhancement of immune function by LPT have been offered, the ability of LPT to enhance killing of bacterial by the immune system has not been quantitatively dened. Nor is it understood to what extent LPT mobilizes immune cells directly from lymphoid tissue to the blood independent of the lymphatic circulation and whether specic lymph pumps impact this mobilization preferentially. Nonetheless, it seems likely that this LPT-mediated increase in immune cells improves immune surveillance, which in turn further boosts protection against infectious disease. Clearly, additional clinical trails and experiments using animal models are required to determine the effectiveness and mechanisms of protection produced by LPT during the treatment of pneumonia.

20

L.M. Hodge
12. Huff JB, Schander A, Downey HF, Hodge LM. Lymphatic pump treatment enhances the lymphatic release of lymphocytes. Lymphat Res Biol 2010;8:183e7. 13. Wallace E, McPartland JM, Jones III JM, Kuchera WA, Buser BR. Lymphatic system: lymphatic manipulative techniques. In: Ward RC, editor. Foundations for osteopathic medicine. 2nd ed. Philadelphia: Lippincott William & Wilkins; 2003. p. 1056e77. 14. Degenhardt BF, Kuchera ML. Update on osteopathic medical concepts and the lymphatic system. J Am Osteopath Assoc 1996;96:97e100. 15. Sefnger MA, King HH, Ward RC, Jones JM, Rogers FJ. Osteopathic philosophy. In: Ward RC, editor. Foundations for osteopathic medicine. Baltimore: Lippincott Williams & Wilkins; 2003. p. 3e12. 16. Allen TW, Pence TK. The use of the thoracic pump in treatment of lower respiratory tract disease. J Am Osteopath Assoc 1967;67:408e11. 17. Kline C. Osteopathic manipulative therapy, antibiotics, and supportive therapy in respiratory infections in children: comparative study. J Am Osteopath Assoc 1965;65:278e81. 18. Noll DR, Degenhardt BF, Morely TF, Blais FX, Hortos KA, Hensel K, et al. Efcacy of osteopathic manipulation as an adjunctive therapy for hospitalized patients with pneumonia: a randomized controlled trial. Osteopath Med Prim Care 2010;4:2. 19. Dery M, Winterson B, Yonuschot G. The effect of lymphatic pump manipulation on the healthy and injured rat. Lymphology 2000;33:58e61. 20. Castlio Y, Ferris-Swift L. Effects of splenic stimulation in normal individuals on the active and differential blood cell counts and the opsonotic index. Kansas City College Osteopath Surg 1932;16:10e6. 21. Mesina J, Hampton D, Evans R, Ziegler T, Mikeska C, Thomas K, et al. Transient basophilia following the application of lymphatic pump techniques: a pilot study. J Am Osteopath Assoc 1998;98:91e4. 22. Castlio Y, Ferris-Swift L. The effect of direct splenic stimulation on the cells and antibody content of the bloodstream in acute infectious disease. Kansas City College Osteopath Surg 1934;18:196e211. 23. Davidson MT, Deitch EA, Lu Q, Osband A, Feketeova E, Ne meth ZH, et al. A study of the biologic activity of traumahemorrhagic shock mesenteric lymph over time and the relative role of cytokines. Surgery 2004;136:32e41. 24. Measel Jr JW. The effect of lymphatic pump on the immune response: preliminary studies on the antibody response to pneumococcal polysaccharide assayed by bacterial agglutination and passive hemagglutination. J Am Osteopath Assoc 1982;82:28e31. 25. Jackson KM, Steele TF, Dugan EP, Kukulka G, Blue W, Roberts A. Effect of lymphatic and splenic pump techniques on the antibody response to Hepatitis B vaccine: a pilot study. J Am Osteopath Assoc 1998;98:155e60. 26. Patterson MM. The Coming Inuenza Pandemic: lessons from the past for the future. J Am Osteopath Assoc 2005; 105:498e500. 27. Yoshikawa TT. Antimicrobial resistance and aging: beginning of the end of the antimicrobial era. J Am Geriatric Soc 2002;50:S226e9. 28. Gao YJ, Ji RR. Light touch induces ERK activation in supercial dorsal horn neurons after inammation: involvement of spinal astrocytes and JNK signaling in touchevoked central sensitization and mechanical allodynia. J Neurochem 2010 October;115:505e14. 29. So PS, Jiang Y, Qin Y. Touch therapies for pain relief in adults. Cochrane Library 2008;4:1e45.

Author disclosure statement

LMH provided the scientic oversight for the data shown in Table 1 and Figures 1 and 2 and prepared the manuscript. No competing nancial interests exist.

Acknowledgements
This research was supported by National Institutes of Health Grant R01 AT004361 (LMH) and the American Osteopathic Association Grants AOA 1011-609 and AOA 06-11-547 (LMH). Lisa M. Hodge would like to thank the Osteopathic Heritage Foundation for their continued support of her position as the Basic Science Research Chair. In addition, she would like to thank Kyle Gummelt, D.O. and Jamie Huff, D.O. for their design and application of the osteopathic manipulations in animals.

References
1. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996;272:60. 2. Olszewski WL. The lymphatic system in body homeostasis: physiological conditions. Lymphat Res Biol 2003;1:11e21. 3. Rockson SD. Lymphedema. Am J Med 2001;110:288e95. 4. Davis MJ, Davis AM, Lane MM, Ku CW, Gashev A. Ratesensitive contractile responses of lymphatic vessels to circumferential stretch. J Physiol 2009;15;587:165e82. 5. Quick CM, Venugopal AM, Dongaonkar RM, Laine GA, Stewart RH. First-order approximation for the pressure-ow relationship of spontaneously contracting lymphangions. Am J Physiol Heart Circ Physiol 2008;294:H2144e9. 6. Knott EM, Tune JD, Stoll ST, Downey HF. Increased lymphatic ow in the thoracic duct during manipulative intervention. J Am Osteopath Assoc 2005;105:447e56. 7. Downey HF, Durgam P, Williams Jr AG, Rajmane A, King HH, Stoll ST. Lymph ow in the thoracic duct of conscious dogs during lymphatic pump treatment, exercise, and expansion of extracellular uid volume. Lymphat Res Biol 2008;6: 3e13. 8. Schad H, Brechtelsbauer H. Thoracic duct lymph ow and composition in conscious dogs and the inuence of anaesthesia and passive limb movement. Pugers Arch 1977;371: 25e31. 9. Hodge LM, King HH, Williams Jr AG, Reder SJ, Belavadi TJ, Simecka JW, et al. Abdominal lymphatic pump treatment increases leukocyte count and ux in thoracic duct lymph. Lymphat Res Biol 2007;5:127e33. 10. Hodge LM, Bearden MK, Schander A, Huff JB, Williams Jr A, King HH, et al. Abdominal lymphatic pump treatment mobilizes leukocytes from the gastrointestinal associated lymphoid tissue into lymph. Lymphat Res Biol 2010;8: 103e10. 11. Schander A, Downey HF, Hodge LM. Lymphatic pump manipulation mobilizes inammatory mediators into lymphatic circulation. J Exp Biol Med; in press.

Osteopathic lymphatic pump techniques to enhance immunity and treat pneumonia

30. Schander A, Gummelt KL, Hodge LM. Lymphatic pump technique facilitates the clearance of respiratory infection with Streptococcus pneumoniae. J Am Osteopath Assoc 2011;111:506e7. 31. Propst-Graham KL, Preheim LC, Vander Top EA, Snitily MU, Gentry-Nielsen MJ. Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae. BMC Microbiol 2007;7:94. 32. Blasi F, Tarsia P, Aliberti S. Strategic targets of essential host-pathogen interactions. Respiration 2005;72:9e25. 33. Preheim LC, Olsen KM, Yue M, Snitily MU, GentryNeilson MJ. Effect of cirrhosis on antibiotic efcacy in a rat model of pneumococcal pneumonia. Diagn Microbiol Infect Dis 2005;51:103e11. 34. Chu CH, David Liu D, Hsu YH, Lee KC, Chen HI. Propofol exerts protective effects on the acute lung injury induced by endotoxin in rats. Pulm Pharmacol Ther 2007;20: 503e12. 35. Chan KC, Lin CJ, Lee PH, Chen CF, Lai YL, Sun WZ, et al. Propofol attenuates the decrease of dynamic compliance and water content in the lung by decreasing oxidative radicals released from the reperfused liver. Anesth Analg 2008 Oct;107:1284e9. 36. Holt PG, Strickland DH, Wikstro m ME, Jahnsen FL. Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol 2008 Feb;8:142e52. 37. Bergeron Yves, Ouellet Nathalie, Deslauriers Anne-Marie, Simard Marie, Olivier Martin, Bergeron Michel G. Cytokine kinetics and other host factors in response to pneumococcal pulmonary infection in mice. Infect Immun 1998;66: 912e22. 38. Nagata M. Inammatory cells and oxygen radicals. Curr Drug Targets Inamm Allergy 2005;4:503e4.

21

39. Simecka JW. Mucosal immunity of the gastrointestinal tract and oral tolerance. Adv Drug Deliv Rev 1998;34:235e59. 40. Takahashi I, Kiyono H. Gut as the largest immunologic tissue. J Parenter Enteral Nutr 1999;23:S7e12. 41. Stokes MG, Titball RW, Neeson BN, Galen JE, Walker NJ, Stagg AJ, et al. Oral administration of a Salmonellae-based vaccine expressing Bacillus anthracis protective antigen confers protection against aerosolized B. anthracis. Infect Immun 2007;75:1827e34. 42. Wallace FJ, Cripps AW, Clancy RL, Husband AJ, Witt CS. A role for intestinal T lymphocytes in bronchus mucosal immunity. Immunol 1991;74:68e73. 43. Zuercher AW, Han-Qing J, Thurnheer CM, Cuff CF, Cebra JJ. Distinct mechanisms for cross-protection of the upper versus lower respiratory tract through intestinal priming. J Immunol 2002;167:3920e5. 44. Sato J, Chida K, Suda T, Naknura H. Migratory patterns of thoracic duct lymphocytes into bronchus-associated tissue of immunized rats. Lung 2000;178:295e308. 45. Paul RT, stomel RJ, Broniak FF, Williams BB. Interferon levels in human subjects throughout a 24-hr period following thoracic lymphatic pump manipulation. J Am Osteopath Assoc 1986;86:92e5. 46. Noll DR, Johnson JC, Baer RW, Snider EJ. The immediate effect of individual manipulation techniques on pulmonary function measures in persons with chronic obstructive pulmonary disease. Osteopath Med Prim Care 2009; 3:9. 47. Noll DR, Degenhardt BF, Stuart MK, Werden S, McGovern RJ, Johnson JC. The effect of osteopathic manipulative treatment on immune response to the inuenza vaccine in nursing homes residents: a pilot study. Altern Ther Health Med 2004;10:74e6.

Available online at www.sciencedirect.com