Accepted Manuscript Remote ischemic preconditioning as prevention of transfusion-related acute lung injury Carlos R. Camara-Lemarroy PII: DOI: Reference:
S0306-9877(14)00220-5 http://dx.doi.org/10.1016/j.mehy.2014.05.016 YMEHY 7615
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
2 January 2014 24 May 2014
Please cite this article as: C.R. Camara-Lemarroy, Remote ischemic preconditioning as prevention of transfusionrelated acute lung injury, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy.2014.05.016
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Remote ischemic preconditioning as prevention of transfusion-related acute lung injury 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Carlos R. Camara-Lemarroy, MD
Affiliation: Departamento de Medicina Interna. Hospital Universitario “Dr. José E. González”. Universidad Autónoma de Nuevo León. Monterrey, N.L. México. Madero y Gonzalitos S/N, Monterrey NL. 64460, México.
Correspondence: Carlos Rodrigo Cámara-Lemarroy, Departamento de Medicina Interna. Hospital Universitario “Dr. José E. González”. Universidad Autónoma de Nuevo León. Monterrey, N.L. México. Madero y Gonzalitos S/N, Monterrey NL. 64460 México. Tel/Fax: (81) 8333-7798. E-mail: [email protected] Telephone/Fax: Tel/Fax:+52 (81) 8333-7798.
Funding: I received no external funding sources
Abstract 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion medicine, considered now as the leading cause of transfusion-related mortality. It may occur in up to 1 in 5,000 transfusions and carries an elevated morbidity and mortality. Clinically it presents as hypoxia and non-cardiogenic pulmonary edema, usually within 6 hours of transfusion. It consists of an immunological phenomenon involving the activation of neutrophils and endothelial injury, leading to capillary leak and pulmonary edema, mechanisms shared with lung ischemia-reperfusion (IR) injury. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIPC). Limb RIP has been shown to protect the lung against IR injury trough modulation of endothelial function as well as neutrophil activation and infiltration. The protective effects of RIPC on the lung have been confirmed in clinical trials of orthopedic and cardiothoracic surgery. RIPC is a safe, tolerable and cheap procedure. I propose that limb RIPC could be used as a preventive strategy against the development of TRALI.
INTRODUCTION
Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion medicine, considered now as the leading cause of transfusion-related mortality. The incidence of TRALI has not been well established, and estimated incidence rates vary widely, ranging from 0.002% to 1.12% per product transfused (1). TRALI causes hypoxia and noncardiogenic pulmonary edema, typically within 6 hours of transfusion. Critically ill patients are at increased risk of developing TRALI, and some intensive care units report TRALI incidences up to 8% (2). There is a higher incidence in plasma and platelet products than in red blood cell products (1:2-300 000 fatal cases for plasma products vs 1:25 000 000 fatal cases for blood cell products), as well as an association
with donor leukocyte antibodies (3). The morbidity and mortality associated with TRALI has led to 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
management strategies such as excluding female donors, excluding plasma and platelet products from donors with leukocyte antibodies among others, all aimed at reducing risk of developing TRALI. However, the risk has not been eliminated. Treatment currently is mainly supportive. Mortality rate associated with TRALI varies according to the reported literature, but appears to be between 5 and 10% (4).
HYPOTHESIS
TRALI is associated with endothelial dysfunction and neutrophil-mediated acute lung injury (ALI). Remote ischemic preconditioning (RIPC) has been shown to modulate these events in the lung. RIPC could be effective in preventing and/or attenuating TRALI.
EVALUATION OF THE HYPOTHESIS
The physiopathology of TRALI is quite complex. Both antibody-dependent and antibodyindependent mechanisms have been described, requiring neutrophil and pulmonary endothelial cell activation (1, 3, 5). Antibody-mediated TRALI requires the infusion of donor leukoagglutinating antibodies (for recipient HLA class I or human neutrophil antigens, for example) that lead to neutrophil activation, endothelial injury and capillary leak (1, 5). Activated neutrophils are sequestered in the lungs and produce cytotoxic mediators such as free radicals and cytokines that perpetuate endothelial damage, translating into ALI.
However, in 10-15% of cases no antibody has been identified. In order to explain these cases, a two-event hypothesis has also been advanced (1-5). The first event is the underlying condition of the patient (sepsis, surgery, massive transfusion) resulting in an insult to the vascular endothelium,
expression of adhesion molecules and endothelial activation, followed by priming of neutrophils. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
The second event is the transfusion of a blood product, after which either antibodies or bioactive lipids (inflammatory mediators and cytokines) activate the primed neutrophils, resulting in pulmonary edema.
These two mechanisms are known to occur and both lead to the common pathway of neutrophil activation, translocation, sequestration and release of inflammatory and cytotoxic mediators. Interestingly, these mechanisms are also central regulators of lung ischemia-reperfusion (IR) injury.
IR injury occurs when blood flow to an organ is interrupted, such as in arterial embolism or thrombosis, during transplant procedures or shock, followed by restoration of blood flow. Lung IR injury remains one of the major complications after cardiac bypass surgery and lung transplantation (6). Neutrophils are important mediators of changes in endothelial and epithelial permeability following lung IR (7). IR in the lung induces proinflammatory cytokine release, causing upregulation of cell-surface adhesion molecules in the pulmonary endothelium. This in turn leads to leukocyte sequestration and polymorphonuclear activation. As a consequence of neutrophil activation and release of metalloproteinases and free radicals, microvascular endothelial cells are activated and become more dysfunctional and more permeable to macromolecules. Neutrophils promote their adherence to the endothelium by increasing the expression of CD18 and CD11b surface adhesion molecules that promote adhesion to specific ligands, such as intercellular adhesion molecule-1 and P-selectin from the endothelium (6, 7). Neutrophils further stimulate adherence by producing multiple proinflammatory cytokines and chemotactic agents and cause direct pulmonary injury by releasing elastase and other proteases. The consequence of these alterations is pulmonary leakage and edema.
Treatments aimed at attenuating IR-injury often involve the inhibition of one or many of these
inflammatory pathways. Ischemic preconditioning (IPC) consists of a brief episode of ischemia that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
precedes the major ischemic event, and leads to the modulation of the innate organ defenses and inflammatory response, leading to decreased resulting injury (8). The molecular mechanisms of IPC are complex, and involve various pathways, such as modulation of inflammatory cytokines, leukocytes (including neutrophils), oxidative stress among others. These events prepare tissues to withstand IR injury, with impressive efficacy.
RIPC has emerged as an interesting alternative to direct IPC. RIPC involves the induction of protection against IR injury in an organ by brief episodes of ischemia and reperfusion in an entirely different organ or limb (9). Circulating mediators and/or signals are hypothesized to mediate this effect, and some mechanisms involved so far are similar to those that applied in direct IPC, including the modulation of neutrophil function. RIPC is less invasive than IP and has led to great clinical interest for its application (10). The induction of forearm or leg IR by the inflation of a blood-pressure cuff for brief episodes (5 minutes) is safe and tolerable and it´s the preferred method in human trials, that has shown promising results in the setting of myocardial ischemia. Attenuation of endothelial cell injury and dysfunction, as well as attenuation of neutrophil infiltration and activity, are central events in the protection afforded against IR injury by RIPC.
Experimental and clinical evidence has shown that RIPC can protect the lung against IR injury. In animal models of limb RIPC as treatment for limb IR-induced remote lung injury, RIPC was able to reduce pulmonary neutrophil infiltration, lung edema, as well as myeloperoxidase and oxidative stress (11, 12). Limb RIPC could also attenuate hemorrhagic-shock induced lung injury by attenuating lung function alterations and significant increases in leukocyte infiltration, water content, inflammation, and lipid peroxidation (13). The pulmonary-protective effects of RIPC have been confirmed in clinical studies. In 30 patients randomized to undergo RIPC before extended torniquete-induced IR injury during lower limb orthopedic surgery, RIPC was shown to improve
arterial-alveolar oxygen tension ratio, reduce respiratory index and attenuate cytokine and free 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
radical release (14). In a randomized clinical trial of arm RIPC before open heart surgery in 60 infants (congenital heart defect corrective surgery) RIPC was shown to reduce inflammatory cytokine release, reduce lung indices, preserve lung compliance and attenuate lung IR injury (15).
RIPC is known to act partially through the modulation of endothelial cells, preserving the integrity of barrier function, cytokine and adhesion molecule expression and transmigration of neutrophils, ultimately reducing leakage and tissue edema (16). Neutrophil function has been shown to be modulated by RIPC in clinical and experimental studies. Kinins are known to be involved in RIPC and act via the G protein coupled B1 and B2 receptors. Interaction of the kinins with their respective receptors in neutrophils causes receptor internalization, thereby reducing the potential for further neutrophil activation. In healthy human volunteers, arm RIPC was able to reduce kinin B1 and B2 receptors after brief forearm ischemia-reperfusion injury (17). In another study involving patients undergoing coronary artery bypass grafting under cardiopulmonary bypass, arm RIPC reduced the expression of kinin B1 and B2 receptors in neutrophils (18). In an animal model of aortic IR, RIPC reduced in vivo recruitment of neutrophils and reduced the expression of P-selectin, E-selectin and ICAM-1(19). Arm IPC in human volunteers prevented endothelial dysfunction and reduced neutrophil CD11b expression and platelet-neutrophil complexes in circulating blood (20).Using a microarray method, arm IPC in human volunteers was shown to reduce the expression of genes encoding for proteins involved in cytokine synthesis, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity signaling pathways, and apoptosis, as well as CD11b expression measured by flow cytometry, in circulating neutrophils (21). In a model of repetitive transient human forearm ischemia RIPC led to reduced neutrophil adhesion, phagocytosis and cytokine release when studied in vitro (22).
CONSEQUENCES OF THE HYPOTHESIS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Limb RIPC is safe, tolerable and can be implemented with minimal equipment and personnel requirements (usually a blood-pressure cuff). The evidence reviewed suggests it can protect the lung against insults involving endothelial injury and neutrophil infiltration/activation. Although TRALI is not predictable, it is a serious condition that occurs after a common clinical indication (transfusions), and therefore amenable to preventive interventions. The hypothesis advanced here is that RIPC could be implemented as a preventive strategy against TRALI, in addition to current preventive strategies. Short cycles of arm RIPC could be induced before transfusions in susceptible patients (critically ill patients, patients with massive transfusions) in order to reduce the incidence or severity of TRALI, by preconditioning the donor to withstand neutrophil-mediated ALI.
The authors declare no conflict of interest
BIBLIOGRAPHY 1. Vlaar AP, Schultz MJ, Juffermans NP. Transfusion-related acute lung injury: a change of perspective. Neth J Med. 2009;67:320-6. 2. Triulzi DJ.Transfusion-related acute lung injury: current concepts for the clinician.Anesth Analg. 2009;108:770-6. 3. Shaz BH, Stowell SR, Hillyer CD. Transfusion-related acute lung injury: from bedside to bench and back. Blood. 2011;117:1463-71. 4. Silliman CC, Fung YL, Ball JB, Khan SY. Transfusion-related acute lung injury (TRALI):
current concepts and misconceptions. Blood Rev. 2009;23:245-55. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
5. West FB, Silliman CC. Transfusion-related acute lung injury: advances in understanding the role of proinflammatory mediators in its genesis. Expert Rev Hematol. 2013;6:265-76. 6. den Hengst WA, Gielis JF, Lin JY, Van Schil PE, De Windt LJ, Moens AL. Lung ischemiareperfusion injury: a molecular and clinical view on a complex pathophysiological process.Am J Physiol Heart Circ Physiol. 2010;299:H1283-99. 7. Schofield ZV, Woodruff TM, Halai R, Wu MC, Cooper MA. Neutrophils-a key component of ischemia-reperfusion injury. Shock. 2013;40:463-70. 8. Otani H. Ischemic preconditioning: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2008;10:207-47. 9. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury--a review. J Surg Res. 2008;150:304-30. 10. Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009;374:1557-65. 11. Olguner C, Koca U, Kar A, et al. Ischemic preconditioning attenuates the lipid peroxidation and remote lung injury in the rat model of unilateral lower limb ischemia reperfusion. Acta Anaesthesiol Scand. 2006;50:150-5. 12. Peng TC, Jan WC, Tsai PS, Huang CJ. Heme oxygenase-1 mediates the protective effects of ischemic preconditioning on mitigating lung injury induced by lower limb ischemiareperfusion in rats. J Surg Res. 2011;167:e245-53. 13. Jan WC, Chen CH, Tsai PS, Huang CJ. Limb ischemic preconditioning mitigates lung injury induced by haemorrhagic shock/resuscitation in rats. Resuscitation. 2011;82:760-6. 14. Lin LN, Wang LR, Wang WT, et al. Ischemic preconditioning attenuates pulmonary
dysfunction after unilateral thigh tourniquet-induced ischemia-reperfusion. Anesth Analg. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
2010;111:539-43. 15. Zhou W, Zeng D, Chen R, et al. Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants. Pediatr Cardiol. 2010;31:22-9. 16. Seal JB, Gewertz BL.Vascular dysfunction in ischemia-reperfusion injury. Ann Vasc Surg. 2005;19:572-84. 17. Saxena P, Shaw OM, Misso NL, et al. Remote ischemic preconditioning stimulus decreases the expression of kinin receptors in human neutrophils. J Surg Res. 2011;171:311-6. 18. Saxena P, Aggarwal S, Misso NL, et al. Remote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery. Interact Cardiovasc Thorac Surg. 2013;17:653-8. 19. Erling N Jr, Nakagawa NK, Costa Cruz JW, et al. Microcirculatory effects of local and remote ischemic preconditioning in supraceliac aortic clamping. J Vasc Surg. 2010;52:13219. 20. Kharbanda RK, Peters M, Walton B, et al. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001;103:1624-30. 21. Konstantinov IE, Arab S, Kharbanda RK, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics. 2004;19:143-50. 22. Shimizu M, Saxena P, Konstantinov IE, et al. Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J Surg Res. 2010;158:155-61.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
FIGURE LEGEND Figure 1. Molecular pathogenesis of Transfusion-related acute lung injury (TRALI) and mechanisms modulated by remote ischemic preconditioning (RIPC). There are multiple pathways involved in the pathophysiology and immunity associated with TRALI. This leads to end organ damage (acute lung injury) as discussed in the text. Both endothelial and neutrophil activation are essential steps in the development of TRALI. (1) RIPC can modulate neutrophil cell infiltration and activity. (2) RIPC can also modulate endothelial activation and adhesion molecule expression. N: Neutrophil; EC: Endothelial Cell.
S0306-9877(14)00220-5 http://dx.doi.org/10.1016/j.mehy.2014.05.016 YMEHY 7615
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
2 January 2014 24 May 2014
Please cite this article as: C.R. Camara-Lemarroy, Remote ischemic preconditioning as prevention of transfusionrelated acute lung injury, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy.2014.05.016
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Remote ischemic preconditioning as prevention of transfusion-related acute lung injury 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Carlos R. Camara-Lemarroy, MD
Affiliation: Departamento de Medicina Interna. Hospital Universitario “Dr. José E. González”. Universidad Autónoma de Nuevo León. Monterrey, N.L. México. Madero y Gonzalitos S/N, Monterrey NL. 64460, México.
Correspondence: Carlos Rodrigo Cámara-Lemarroy, Departamento de Medicina Interna. Hospital Universitario “Dr. José E. González”. Universidad Autónoma de Nuevo León. Monterrey, N.L. México. Madero y Gonzalitos S/N, Monterrey NL. 64460 México. Tel/Fax: (81) 8333-7798. E-mail: [email protected] Telephone/Fax: Tel/Fax:+52 (81) 8333-7798.
Funding: I received no external funding sources
Abstract 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion medicine, considered now as the leading cause of transfusion-related mortality. It may occur in up to 1 in 5,000 transfusions and carries an elevated morbidity and mortality. Clinically it presents as hypoxia and non-cardiogenic pulmonary edema, usually within 6 hours of transfusion. It consists of an immunological phenomenon involving the activation of neutrophils and endothelial injury, leading to capillary leak and pulmonary edema, mechanisms shared with lung ischemia-reperfusion (IR) injury. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIPC). Limb RIP has been shown to protect the lung against IR injury trough modulation of endothelial function as well as neutrophil activation and infiltration. The protective effects of RIPC on the lung have been confirmed in clinical trials of orthopedic and cardiothoracic surgery. RIPC is a safe, tolerable and cheap procedure. I propose that limb RIPC could be used as a preventive strategy against the development of TRALI.
INTRODUCTION
Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion medicine, considered now as the leading cause of transfusion-related mortality. The incidence of TRALI has not been well established, and estimated incidence rates vary widely, ranging from 0.002% to 1.12% per product transfused (1). TRALI causes hypoxia and noncardiogenic pulmonary edema, typically within 6 hours of transfusion. Critically ill patients are at increased risk of developing TRALI, and some intensive care units report TRALI incidences up to 8% (2). There is a higher incidence in plasma and platelet products than in red blood cell products (1:2-300 000 fatal cases for plasma products vs 1:25 000 000 fatal cases for blood cell products), as well as an association
with donor leukocyte antibodies (3). The morbidity and mortality associated with TRALI has led to 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
management strategies such as excluding female donors, excluding plasma and platelet products from donors with leukocyte antibodies among others, all aimed at reducing risk of developing TRALI. However, the risk has not been eliminated. Treatment currently is mainly supportive. Mortality rate associated with TRALI varies according to the reported literature, but appears to be between 5 and 10% (4).
HYPOTHESIS
TRALI is associated with endothelial dysfunction and neutrophil-mediated acute lung injury (ALI). Remote ischemic preconditioning (RIPC) has been shown to modulate these events in the lung. RIPC could be effective in preventing and/or attenuating TRALI.
EVALUATION OF THE HYPOTHESIS
The physiopathology of TRALI is quite complex. Both antibody-dependent and antibodyindependent mechanisms have been described, requiring neutrophil and pulmonary endothelial cell activation (1, 3, 5). Antibody-mediated TRALI requires the infusion of donor leukoagglutinating antibodies (for recipient HLA class I or human neutrophil antigens, for example) that lead to neutrophil activation, endothelial injury and capillary leak (1, 5). Activated neutrophils are sequestered in the lungs and produce cytotoxic mediators such as free radicals and cytokines that perpetuate endothelial damage, translating into ALI.
However, in 10-15% of cases no antibody has been identified. In order to explain these cases, a two-event hypothesis has also been advanced (1-5). The first event is the underlying condition of the patient (sepsis, surgery, massive transfusion) resulting in an insult to the vascular endothelium,
expression of adhesion molecules and endothelial activation, followed by priming of neutrophils. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
The second event is the transfusion of a blood product, after which either antibodies or bioactive lipids (inflammatory mediators and cytokines) activate the primed neutrophils, resulting in pulmonary edema.
These two mechanisms are known to occur and both lead to the common pathway of neutrophil activation, translocation, sequestration and release of inflammatory and cytotoxic mediators. Interestingly, these mechanisms are also central regulators of lung ischemia-reperfusion (IR) injury.
IR injury occurs when blood flow to an organ is interrupted, such as in arterial embolism or thrombosis, during transplant procedures or shock, followed by restoration of blood flow. Lung IR injury remains one of the major complications after cardiac bypass surgery and lung transplantation (6). Neutrophils are important mediators of changes in endothelial and epithelial permeability following lung IR (7). IR in the lung induces proinflammatory cytokine release, causing upregulation of cell-surface adhesion molecules in the pulmonary endothelium. This in turn leads to leukocyte sequestration and polymorphonuclear activation. As a consequence of neutrophil activation and release of metalloproteinases and free radicals, microvascular endothelial cells are activated and become more dysfunctional and more permeable to macromolecules. Neutrophils promote their adherence to the endothelium by increasing the expression of CD18 and CD11b surface adhesion molecules that promote adhesion to specific ligands, such as intercellular adhesion molecule-1 and P-selectin from the endothelium (6, 7). Neutrophils further stimulate adherence by producing multiple proinflammatory cytokines and chemotactic agents and cause direct pulmonary injury by releasing elastase and other proteases. The consequence of these alterations is pulmonary leakage and edema.
Treatments aimed at attenuating IR-injury often involve the inhibition of one or many of these
inflammatory pathways. Ischemic preconditioning (IPC) consists of a brief episode of ischemia that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
precedes the major ischemic event, and leads to the modulation of the innate organ defenses and inflammatory response, leading to decreased resulting injury (8). The molecular mechanisms of IPC are complex, and involve various pathways, such as modulation of inflammatory cytokines, leukocytes (including neutrophils), oxidative stress among others. These events prepare tissues to withstand IR injury, with impressive efficacy.
RIPC has emerged as an interesting alternative to direct IPC. RIPC involves the induction of protection against IR injury in an organ by brief episodes of ischemia and reperfusion in an entirely different organ or limb (9). Circulating mediators and/or signals are hypothesized to mediate this effect, and some mechanisms involved so far are similar to those that applied in direct IPC, including the modulation of neutrophil function. RIPC is less invasive than IP and has led to great clinical interest for its application (10). The induction of forearm or leg IR by the inflation of a blood-pressure cuff for brief episodes (5 minutes) is safe and tolerable and it´s the preferred method in human trials, that has shown promising results in the setting of myocardial ischemia. Attenuation of endothelial cell injury and dysfunction, as well as attenuation of neutrophil infiltration and activity, are central events in the protection afforded against IR injury by RIPC.
Experimental and clinical evidence has shown that RIPC can protect the lung against IR injury. In animal models of limb RIPC as treatment for limb IR-induced remote lung injury, RIPC was able to reduce pulmonary neutrophil infiltration, lung edema, as well as myeloperoxidase and oxidative stress (11, 12). Limb RIPC could also attenuate hemorrhagic-shock induced lung injury by attenuating lung function alterations and significant increases in leukocyte infiltration, water content, inflammation, and lipid peroxidation (13). The pulmonary-protective effects of RIPC have been confirmed in clinical studies. In 30 patients randomized to undergo RIPC before extended torniquete-induced IR injury during lower limb orthopedic surgery, RIPC was shown to improve
arterial-alveolar oxygen tension ratio, reduce respiratory index and attenuate cytokine and free 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
radical release (14). In a randomized clinical trial of arm RIPC before open heart surgery in 60 infants (congenital heart defect corrective surgery) RIPC was shown to reduce inflammatory cytokine release, reduce lung indices, preserve lung compliance and attenuate lung IR injury (15).
RIPC is known to act partially through the modulation of endothelial cells, preserving the integrity of barrier function, cytokine and adhesion molecule expression and transmigration of neutrophils, ultimately reducing leakage and tissue edema (16). Neutrophil function has been shown to be modulated by RIPC in clinical and experimental studies. Kinins are known to be involved in RIPC and act via the G protein coupled B1 and B2 receptors. Interaction of the kinins with their respective receptors in neutrophils causes receptor internalization, thereby reducing the potential for further neutrophil activation. In healthy human volunteers, arm RIPC was able to reduce kinin B1 and B2 receptors after brief forearm ischemia-reperfusion injury (17). In another study involving patients undergoing coronary artery bypass grafting under cardiopulmonary bypass, arm RIPC reduced the expression of kinin B1 and B2 receptors in neutrophils (18). In an animal model of aortic IR, RIPC reduced in vivo recruitment of neutrophils and reduced the expression of P-selectin, E-selectin and ICAM-1(19). Arm IPC in human volunteers prevented endothelial dysfunction and reduced neutrophil CD11b expression and platelet-neutrophil complexes in circulating blood (20).Using a microarray method, arm IPC in human volunteers was shown to reduce the expression of genes encoding for proteins involved in cytokine synthesis, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity signaling pathways, and apoptosis, as well as CD11b expression measured by flow cytometry, in circulating neutrophils (21). In a model of repetitive transient human forearm ischemia RIPC led to reduced neutrophil adhesion, phagocytosis and cytokine release when studied in vitro (22).
CONSEQUENCES OF THE HYPOTHESIS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Limb RIPC is safe, tolerable and can be implemented with minimal equipment and personnel requirements (usually a blood-pressure cuff). The evidence reviewed suggests it can protect the lung against insults involving endothelial injury and neutrophil infiltration/activation. Although TRALI is not predictable, it is a serious condition that occurs after a common clinical indication (transfusions), and therefore amenable to preventive interventions. The hypothesis advanced here is that RIPC could be implemented as a preventive strategy against TRALI, in addition to current preventive strategies. Short cycles of arm RIPC could be induced before transfusions in susceptible patients (critically ill patients, patients with massive transfusions) in order to reduce the incidence or severity of TRALI, by preconditioning the donor to withstand neutrophil-mediated ALI.
The authors declare no conflict of interest
BIBLIOGRAPHY 1. Vlaar AP, Schultz MJ, Juffermans NP. Transfusion-related acute lung injury: a change of perspective. Neth J Med. 2009;67:320-6. 2. Triulzi DJ.Transfusion-related acute lung injury: current concepts for the clinician.Anesth Analg. 2009;108:770-6. 3. Shaz BH, Stowell SR, Hillyer CD. Transfusion-related acute lung injury: from bedside to bench and back. Blood. 2011;117:1463-71. 4. Silliman CC, Fung YL, Ball JB, Khan SY. Transfusion-related acute lung injury (TRALI):
current concepts and misconceptions. Blood Rev. 2009;23:245-55. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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FIGURE LEGEND Figure 1. Molecular pathogenesis of Transfusion-related acute lung injury (TRALI) and mechanisms modulated by remote ischemic preconditioning (RIPC). There are multiple pathways involved in the pathophysiology and immunity associated with TRALI. This leads to end organ damage (acute lung injury) as discussed in the text. Both endothelial and neutrophil activation are essential steps in the development of TRALI. (1) RIPC can modulate neutrophil cell infiltration and activity. (2) RIPC can also modulate endothelial activation and adhesion molecule expression. N: Neutrophil; EC: Endothelial Cell.
