Macrophages and post-burn immune dysfunction

doi:10.1016/S0305-4179(02)00187-0

Burns

Volume 29, Issue 1, February 2003, Pages 1-14

https://doi.org/10.1016/S0305-4179(02)00187-0 Get rights and content

Abstract

The activation of a pro-inflammatory cascade after burn injury appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. Macrophages are major producers of pro-inflammatory mediators and their productive capacity for these mediators is markedly enhanced following thermal injury. Thus, macrophage hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) appears to be of critical importance in the development of post-burn immune dysfunction. This review will focus on the current state of knowledge with regards to the role of macrophages in the development of post-burn immune dysfunction. Particular areas of discussion include: nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, macrophages and the T-helper (Th)-1/Th-2 cytokine responses, alterations in macrophages signal transduction and a potential role for γ/δ T-cells in the development of macrophage hyperactivity following thermal injury. A more comprehensive understanding of the relationship between macrophage activity and post-burn immune dysfunction will hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients.

Introduction

While current procedures for burn injury management have improved patient prognosis, increased morbidity and mortality remain major concerns. Thus, identification of the mechanisms responsible for post-burn immune dysfunction and increased susceptibility to subsequent sepsis and multiple organ failure under such conditions are essential for the development of improved treatment modalities.

Thermal injury induces an immunosuppressed state that predisposes patients to sepsis and multiple organ failure [1], [2], [3], [4], [5], [6]. These are major complications associated with burn trauma and recent evidence suggests that activation of a pro-inflammatory cascade plays an important role in their development [7]. With regard to this, macrophages (Mφ) are major producers of pro-inflammatory mediators (i.e. prostaglandin E₂ (PGE₂), reactive nitrogen intermediates (RNI), interleukin (IL)-6, tumor necrosis factor-α (TNF-α)) [8], [9]. Moreover, thermal injury increases the productive capacity of Mφ for these mediators [10], [11], [12], [13]. Dysregulation of Mφ activity leading to increased release of pro-inflammatory factors (i.e. Mφ hyperactivity), appears to be of fundamental importance in the development of post-burn immune dysfunction [14]. Therefore, identification of the mediators and mechanisms by which thermal injury induces alterations in Mφ activity, leading to expression of a “hyperactive” phenotype is of significant interest. Nonetheless, while studies strongly support Mφ hyperactivity as a causative factor in post-burn immune dysfunction additional factors also appear to contribute including T-cell dysfunction [15], glucocorticoids [16] and T-helper (Th)-2 cytokines [17]. This review will focus on the current state of knowledge concerning the role of Mφ in the development of post-burn immune dysfunction.

Section snippets

Macrophage hyperactivity

Macrophages play a pivotal role in the immune response, having multiple functions that can both up- and down-regulate host defense mechanisms. Many of these effector functions are not constitutively expressed by the Mφ but are induced in response to specific stimuli such as lipopolysaccharide (LPS), cytokines, such as interferon (IFN)-γ, as well as other factors. Under normal physiological conditions, the Mφ capacity to express these functions is limited; however, if the response of the Mφ to

Signal transduction and macrophage hyperactivity

Recent studies [12], [104] suggest that Mφ hyperactivity post-burn is related to alterations in intracellular cAMP. It is well known that cAMP, a second messenger produced by cell surface receptor activation, mediates most of its effects via activation of cAMP-dependent kinases (PKA) leading to phosphorylation of intracellular proteins (Fig. 1). A number of different cell receptor/ligand interactions (e.g. PGE₂ and β-adrenergic) can elevate intracellular cAMP. Relative to thermal injury,

Macrophages and the Th-1/Th-2 response

T-helper cells have been categorized with regard to their cytokine profile. Th-1 cytokines (IL-2, IFN-γ) support cell-mediated immune responses whereas Th-2 cytokines support humoral immune responses. The regulated induction of Th-1 and Th-2 cytokine expressing lymphocytes is central to the expression of both beneficial and pathological immune responses. With regard to Mφ, Th-1 cytokines support activation, whereas Th-2 cytokines are, in general, suppressive. Mφ also support the differential

γ/δ T-cells and post-burn immune dysfunction

The elevated production of PGE₂ and RNI by Mφ can suppress T-cell activity [66], [153], [154], [155], which has been implicated in post-burn immunosuppression. Therefore, whereas impaired T-cell function may be the endpoint in the development of thermal injury-induced immunosuppression, it appears that Mφ hyperactivity may be an important causative factor. Experimental and clinical studies that have examined the effect of thermal injury of T-cell function have primarily used T-cells purified

Burn wound excision and grafting

Burn wound excision and grafting is a clinical practice that appears to result in decreased complications and improved survival [183], [184], [185], [186], [187]. Age, however, appears to be an important factor in the success of this procedure. In children, the beneficial effect of this procedure in is independent of the aggressiveness of the surgery. For example, Wolf et al. [187] have shown positive effects with massive and total excision of the wound within 48 h, whereas Tompkins et al. [186]

Summary

Major thermal injury occurs at an alarming frequency in the United States with greater than 2 million cases per year. Despite recent advances, compromised immune function resulting in increased susceptibility to subsequent sepsis and multiple organ failure remains a major cause of burn morbidity and mortality. While extensive work has been done to elucidate the mechanisms for immune dysfunction following thermal injury, significant questions remain. With regards to this, Mφ have been suggested

Acknowledgements

Funding from NIH grants GM58242 and IA049960 awarded to MGS supported this work.

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ReviewMacrophages and post-burn immune dysfunction

Abstract

Introduction

Section snippets

Macrophage hyperactivity

Signal transduction and macrophage hyperactivity

Macrophages and the Th-1/Th-2 response

γ/δ T-cells and post-burn immune dysfunction

Burn wound excision and grafting

Summary

Acknowledgements

Burns

Cytokine

Vaccine

Cytokine

Cell Immunol.

Burns

Surgery

Surgery

Immunol. Lett.

Burns

Burns

Curr. Opin. Immunol.

Prostaglandins

Cell Immunol.

Nitric Oxide

J. Surg. Res.

Clin. Lab. Med.

J. Biol. Chem.

Blood

Burns

Impairment of T cell activation in burn patients: a possible mechanism of thermal injury induced immunosuppression

Clin. Exp. Immunol.

Multiple organ failure in patients with thermal injury

Crit. Care Med.

Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle?

Shock

Current treatment of severely burned patients

Ann. Surg.

The immune response to trauma

Semin. Pediatr. Surg.

Etiology of multiple organ failure

J. Trauma

Nitric oxide and macrophage function

Ann. Rev. Immunol.

Thermal injury induced immunosuppression in mice: the role of macrophage derived reactive nitrogen intermediates

J. Leukoc. Biol.

Time course of production of cytokines and prostaglandin E2 by macrophages isolated after thermal injury and bacterial translocation

Circ. Shock

Mechanisms of increased tumor necrosis factor production after thermal injury. Altered sensitivity to PGE2 and immunomodulation by indomethacin

J. Immunol.

Thermal injury induces macrophage hyperactivity through pretussis toxin-sensitive and -insensitive pathways

Shock

Temporal correlation of impaired immune response after thermal injury with susceptibility to infection in a murine model

Surgery

Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection

Ann. Surg.

The production of tumor necrosis factor, interleukin 1, interleukin 6, and prostaglandin E2 by isolated enterocytes and gut macrophages: effect of lipopolysaccaride and thermal injury

J. Burn Care Rehabil.

Mechanisms of altered monocyte prostaglandin E2 production in severely injured patients

Arch. Surg.

Plasma concentrations of type II phospholipase A2, cytokines, ecosinoids in patients with burns

Burns

Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality

Surg. Gynecol. Obstet.

Burn-induced nitric oxide release in humans

J. Trauma

Nitric oxide production is increased in patients after burn injury

J. Trauma

Modulation of macrophage hyperactivity improves survival in a burn-sepsis model

Arch. Surg.

Multiple organ failure: pathophysiology and potential future therapy

Ann. Surg.

Blocking prostaglandin E2 after trauma attenuates pro-inflammatory cytokines and improves survival

Shock

Effect of surgical trauma on splenocyte and peritoneal macrophage immune function

J. Trauma

The immunologic consequences of hemorrhagic shock

Crit. Care Shock

The complex pattern of cytokines in sepsis. Association between prostaglandins, cachectin and interleukins

Review
Macrophages and post-burn immune dysfunction

Time course of production of cytokines and prostaglandin E₂ by macrophages isolated after thermal injury and bacterial translocation

Mechanisms of increased tumor necrosis factor production after thermal injury. Altered sensitivity to PGE₂ and immunomodulation by indomethacin

The production of tumor necrosis factor, interleukin 1, interleukin 6, and prostaglandin E₂ by isolated enterocytes and gut macrophages: effect of lipopolysaccaride and thermal injury

Mechanisms of altered monocyte prostaglandin E₂ production in severely injured patients

Plasma concentrations of type II phospholipase A₂, cytokines, ecosinoids in patients with burns

Blocking prostaglandin E₂ after trauma attenuates pro-inflammatory cytokines and improves survival