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September 1996, Vol 131, No. 9 >
ARTICLE | September 1996

Immune Function Is More Compromised After Closed Bone Fracture and Hemorrhagic Shock Than Hemorrhage Alone FREE

Matthias W. Wichmann, MD; René Zellweger, MD; Catherine M. DeMaso, MS; Alfred Ayala, PhD; Christine Williams, BVSc, MRCVS; Irshad H. Chaudry, PhD
Arch Surg. 1996;131(9):995-1000. doi:10.1001/archsurg.1996.01430210093021
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Objective:  To determine whether closed bone fracture in conjunction with hemorrhagic shock compromises immune functions more severely than hemorrhagic shock alone.

Design:  In a randomized, controlled trial, closed bone fracture of the right lower leg and/or hemorrhagic shock (mean±SEM arterial blood pressure, 35±5 mm Hg for 90 minutes) were induced in male C3H/HeN mice (weight, 25 g). Animals subjected to hemorrhage were resuscitated with the shed blood and lactated Ringer solution. At 72 hours after the experiment, all animals were killed to obtain whole blood, splenocytes, and splenic and peritoneal macrophages. Macrophage interleukin-1 and splenocyte interleukin-2 and interleukin-3 release were determined by bioassay, and splenocyte proliferation was measured by tritiated thymidine incorporation.

Results:  Closed bone fracture alone did not affect immune functions 72 hours after the trauma. Hemorrhagic shock, however, induced a significant depression of splenocyte and macrophage functions. Bone fracture followed by hemorrhagic shock further depressed splenocyte proliferation and splenocyte interleukin-2 and interleukin-3 release as well as interleukin-1 release.

Conclusion:  Since bone injury coupled with hemorrhagic shock produces more severe depression of immune functions than hemorrhage alone, bone injury appears to play a contributory role in further depressing immune functions in trauma patients who experience major blood loss.Arch Surg. 1996;131:995-1000

REFERENCES

1 +
Trunkey DD.  Trauma . Sci Am . 1983;;249:28-35.
2 +
Tylman D, Siwek W.  Long-term results of functional treatment in intra-articular knee fractures and multifragment fractures of the shaft of femurs . Clin Orthop Rel Res . 1991;;272:114-121.
3 +
Faist E, Baue AE, Dittmer H.  Multiple organ failure in polytrauma patients . J Trauma . 1983;;23:775-787.
4 +
Baker CC, Oppenheimer L, Lewis FR, Trunkey DD.  The epidemiology of trauma death . Am J Surg . 1980;;140:144-150.
5 +
Chaudry IH, Ayala A. Immunological Aspects of Hemorrhage . Austin, Tex: Medical Intelligence Unit, RG Landes Co; 1992;:1-132.
6 +
Alexander JW.  Mechanism of immunologic suppression in burn injury . J Trauma . 1990;;30:S70-S75.
7 +
Howard RJ.  Effect of burn injury, mechanical trauma, and operation on immune defenses . Surg Clin North Am . 1979;;59:199-211.
8 +
Miller SE, Miller CL, Trunkey DD.  The immune consequences of trauma . Surg Clin North Am . 1982;;62:167-181.
9 +
Faist E, Kupper TS, Baker CC, Chaudry IH, Dwyer J, Baue AE.  Depression of cellular immunity after major injury: its association with posttraumatic complications and its restoration with immunomodulatory agents . Arch Surg . 1986;; 121:1000-1005.
10 +
Carrico CJ, Meakins JL, Marshall JC, Fry D, Maier RV.  Multiple organ failure syndrome . Arch Surg . 1986;;121:196-203.
11 +
Deitch EA.  Multiple organ failure: pathophysiology and potential future therapy . Ann Surg . 1992;;216:117-134.
12 +
DeCamp MM, Demling RH.  Post-traumatic multisystem organ failure . JAMA . 1988;;260:530-534.
13 +
Chaudry IH, Ayala A, Ertel W, Stephan RN.  Hemorrhage and resuscitation: immunological aspects . Am J Physiol . 1990;;259:R663-R678.
14 +
Ayala A, Lehman DL, Herdon CD, Chaudry IH.  Mechanism of enhanced susceptibility to sepsis following hemorrhage: interleukin (IL)-10 suppression of T-cell response is mediated by eicosanoid induced IL-4 release . Arch Surg . 1994;;129:1172-1178.
15 +
Stephan RN, Kupper TS, Geha AS, Baue AS, Chaudry IH.  Hemorrhage without tissue trauma produces immunosuppression and enhances susceptibility to sepsis . Arch Surg . 1987;;122:62-68.
16 +
Ayala A, Perrin MM, Chaudry IH.  Defective macrophage antigen presentation following haemorrhage is associated with the loss of MHC class II (a) antigens . Immunology . 1990;;70:33-39.
17 +
Zellweger R, Ayala A, DeMaso CM, Chaudry IH.  Trauma-hemorrhage causes prolonged depression in cellular immunity . Shock . 1995;;4:149-153.
18 +
Stephan RN, Mitsuyoski S, Conrad PJ, Dean RE, Geha AS, Chaudry IH.  Depressed antigen presentation function and membrane interleukin-1 activity of peritoneal macrophages after laparotomy . Surgery . 1987;;102:147-154.
19 +
Schmand JF, Ayala A, Morrison MH, Chaudry IH.  Dextran 70 administration following trauma and hemorrhagic shock does not impair cellular immune functions . J Crit Care . 1994;;9:244-256.
20 +
Ayala A, Perrin MM, Wagner MA, Chaudry IH.  Enhanced susceptibility to sepsis following simple hemorrhage: depression of Fc and C3b receptor mediated phagocytosis . Arch Surg . 1990;;125:70-75.
21 +
Ihle JN, Keller J, Greenberger JS, Henderson L, Yetter RA, Morse HC.  Phenotypic characteristics of cell lines requiring IL-3 for growth . J Immunol . 1982;; 129:1377-1383.
22 +
Meldrum DR, Ayala A, Perrin MM, Ertel W, Chaudry IH.  Diltiazem restores IL-2, IL-3, IL-6 and IFN-gamma synthesis and decreases susceptibility to sepsis following hemorrhage . J Surg Res . 1991;;51:158-164.
23 +
Mizel SB.  Production and quantitation of lymphocyte-activating factor (interleukin 1) . In: Herscowitz HB, Holden HT, Bellanti JA, Ghaffar A, eds. Manual of Macrophage Methodology . New York, NY: Marcel Dekker Inc; 1981;:407-441.
24 +
Ertel W, Morrison MH, Ayala A, Chaudry IH.  Chloroquine attenuates hemorrhagic shock induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression through blockade of tumor necrosis factor and prostaglandin release . Blood . 1991;;78:1781-1788.
25 +
Schirmer WJ, Schirmer JM, Townsend MC, Fry DE.  Femur fracture with associated soft-tissue injury produces hepatic ischemia . Arch Surg . 1988;:123: 412-415.
26 +
Shavit Y, Depaulis A, Martin FC, et al.  Involvement of brain opiate receptors in the immune-suppressive effect of morphine . Proc Natl Acad Sci U S A . 1986;; 83:7114-7117.
27 +
Gilman SC, Schwartz JM, Milner RJ, Bloom FE, Feldman JD.  β-Endorphin enhances lymphocyte proliferative responses . Neurobiology . 1982;;79:4226-4230.
28 +
Shires GT.  Evolution of trauma and trauma research . J Trauma . 1990;;30:S107-S115.
29 +
O'Mahony JB, Palder Sb, Wood JJ, et al.  Depression of cellular immunity after multiple trauma in the absence of sepsis . J Trauma . 1984;;24:869-875.
30 +
Hofmann S, Huemer G, Kratochwill C, et al.  Pathophysiology of fat embolisms in orthopedics and traumatology . Orthopade . 1995;;24:84-93.
31 +
Ayala A, Perrin MM, Meldrum DR, Ertel W, Chaudry IH.  Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin . Cytokine . 1990;;2:170-174.
32 +
Bradshaw M, Rutherford MS, Hoeper BJ, et al.  Specific transcriptional inhibition of bone marrow-derived macrophage tumor necrosis factor-α gene expression and protein production using novel enantiomeric carbocyclic nucleoside analogues . J Pharmacol Exp Ther . 1995;;273:1506-1518.
33 +
Hecht M, Muller M, Lohmann-Matthes ML, Emmendorffer A.  In vitro and in vivo effects of pentoxifylline on macrophages and lymphocytes derived from autoimmune MRL.-lpr/lpr mice . J Leukocyte Biol . 1995;;57:242-249.

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1 +
Trunkey DD.  Trauma . Sci Am . 1983;;249:28-35.
2 +
Tylman D, Siwek W.  Long-term results of functional treatment in intra-articular knee fractures and multifragment fractures of the shaft of femurs . Clin Orthop Rel Res . 1991;;272:114-121.
3 +
Faist E, Baue AE, Dittmer H.  Multiple organ failure in polytrauma patients . J Trauma . 1983;;23:775-787.
4 +
Baker CC, Oppenheimer L, Lewis FR, Trunkey DD.  The epidemiology of trauma death . Am J Surg . 1980;;140:144-150.
5 +
Chaudry IH, Ayala A. Immunological Aspects of Hemorrhage . Austin, Tex: Medical Intelligence Unit, RG Landes Co; 1992;:1-132.
6 +
Alexander JW.  Mechanism of immunologic suppression in burn injury . J Trauma . 1990;;30:S70-S75.
7 +
Howard RJ.  Effect of burn injury, mechanical trauma, and operation on immune defenses . Surg Clin North Am . 1979;;59:199-211.
8 +
Miller SE, Miller CL, Trunkey DD.  The immune consequences of trauma . Surg Clin North Am . 1982;;62:167-181.
9 +
Faist E, Kupper TS, Baker CC, Chaudry IH, Dwyer J, Baue AE.  Depression of cellular immunity after major injury: its association with posttraumatic complications and its restoration with immunomodulatory agents . Arch Surg . 1986;; 121:1000-1005.
10 +
Carrico CJ, Meakins JL, Marshall JC, Fry D, Maier RV.  Multiple organ failure syndrome . Arch Surg . 1986;;121:196-203.
11 +
Deitch EA.  Multiple organ failure: pathophysiology and potential future therapy . Ann Surg . 1992;;216:117-134.
12 +
DeCamp MM, Demling RH.  Post-traumatic multisystem organ failure . JAMA . 1988;;260:530-534.
13 +
Chaudry IH, Ayala A, Ertel W, Stephan RN.  Hemorrhage and resuscitation: immunological aspects . Am J Physiol . 1990;;259:R663-R678.
14 +
Ayala A, Lehman DL, Herdon CD, Chaudry IH.  Mechanism of enhanced susceptibility to sepsis following hemorrhage: interleukin (IL)-10 suppression of T-cell response is mediated by eicosanoid induced IL-4 release . Arch Surg . 1994;;129:1172-1178.
15 +
Stephan RN, Kupper TS, Geha AS, Baue AS, Chaudry IH.  Hemorrhage without tissue trauma produces immunosuppression and enhances susceptibility to sepsis . Arch Surg . 1987;;122:62-68.
16 +
Ayala A, Perrin MM, Chaudry IH.  Defective macrophage antigen presentation following haemorrhage is associated with the loss of MHC class II (a) antigens . Immunology . 1990;;70:33-39.
17 +
Zellweger R, Ayala A, DeMaso CM, Chaudry IH.  Trauma-hemorrhage causes prolonged depression in cellular immunity . Shock . 1995;;4:149-153.
18 +
Stephan RN, Mitsuyoski S, Conrad PJ, Dean RE, Geha AS, Chaudry IH.  Depressed antigen presentation function and membrane interleukin-1 activity of peritoneal macrophages after laparotomy . Surgery . 1987;;102:147-154.
19 +
Schmand JF, Ayala A, Morrison MH, Chaudry IH.  Dextran 70 administration following trauma and hemorrhagic shock does not impair cellular immune functions . J Crit Care . 1994;;9:244-256.
20 +
Ayala A, Perrin MM, Wagner MA, Chaudry IH.  Enhanced susceptibility to sepsis following simple hemorrhage: depression of Fc and C3b receptor mediated phagocytosis . Arch Surg . 1990;;125:70-75.
21 +
Ihle JN, Keller J, Greenberger JS, Henderson L, Yetter RA, Morse HC.  Phenotypic characteristics of cell lines requiring IL-3 for growth . J Immunol . 1982;; 129:1377-1383.
22 +
Meldrum DR, Ayala A, Perrin MM, Ertel W, Chaudry IH.  Diltiazem restores IL-2, IL-3, IL-6 and IFN-gamma synthesis and decreases susceptibility to sepsis following hemorrhage . J Surg Res . 1991;;51:158-164.
23 +
Mizel SB.  Production and quantitation of lymphocyte-activating factor (interleukin 1) . In: Herscowitz HB, Holden HT, Bellanti JA, Ghaffar A, eds. Manual of Macrophage Methodology . New York, NY: Marcel Dekker Inc; 1981;:407-441.
24 +
Ertel W, Morrison MH, Ayala A, Chaudry IH.  Chloroquine attenuates hemorrhagic shock induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression through blockade of tumor necrosis factor and prostaglandin release . Blood . 1991;;78:1781-1788.
25 +
Schirmer WJ, Schirmer JM, Townsend MC, Fry DE.  Femur fracture with associated soft-tissue injury produces hepatic ischemia . Arch Surg . 1988;:123: 412-415.
26 +
Shavit Y, Depaulis A, Martin FC, et al.  Involvement of brain opiate receptors in the immune-suppressive effect of morphine . Proc Natl Acad Sci U S A . 1986;; 83:7114-7117.
27 +
Gilman SC, Schwartz JM, Milner RJ, Bloom FE, Feldman JD.  β-Endorphin enhances lymphocyte proliferative responses . Neurobiology . 1982;;79:4226-4230.
28 +
Shires GT.  Evolution of trauma and trauma research . J Trauma . 1990;;30:S107-S115.
29 +
O'Mahony JB, Palder Sb, Wood JJ, et al.  Depression of cellular immunity after multiple trauma in the absence of sepsis . J Trauma . 1984;;24:869-875.
30 +
Hofmann S, Huemer G, Kratochwill C, et al.  Pathophysiology of fat embolisms in orthopedics and traumatology . Orthopade . 1995;;24:84-93.
31 +
Ayala A, Perrin MM, Meldrum DR, Ertel W, Chaudry IH.  Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin . Cytokine . 1990;;2:170-174.
32 +
Bradshaw M, Rutherford MS, Hoeper BJ, et al.  Specific transcriptional inhibition of bone marrow-derived macrophage tumor necrosis factor-α gene expression and protein production using novel enantiomeric carbocyclic nucleoside analogues . J Pharmacol Exp Ther . 1995;;273:1506-1518.
33 +
Hecht M, Muller M, Lohmann-Matthes ML, Emmendorffer A.  In vitro and in vivo effects of pentoxifylline on macrophages and lymphocytes derived from autoimmune MRL.-lpr/lpr mice . J Leukocyte Biol . 1995;;57:242-249.

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