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Inflammatory Response: Current ConceptsEdward R. Sherwood, M.D., Ph.D. Galveston, Texas

316Page 1

Introduction.

Inflammation plays an important role in many pathophysiological processes encountered byanesthesiologists on a daily basis. Surgery, major trauma, sepsis and critical illness all have major inflammatorycomponents. This review will address the basic mechanisms of inflammation and the pathophysiology of inflammation-associated disease processes such as sepsis and the systemic inflammatory response syndrome. Areview of anti-inflammatory therapy and strategies to decrease inflammatory injury will also be discussed.

The Biology of Inflammation.

Inflammation is a mostly beneficial process that functions to remove sources of injury from the host andfacilitate tissue repair. Acute inflammation occurs over a period of hours to days in response to infection or tissueinjury. This process is characterized by local vasodilation, fluid exudation and leukocyte migration into the site of inflammation. In most cases, acute inflammation is self-limited and resolves once the inciting stimulus has beenremoved and repair completed. Chronic inflammation may persist for weeks, months or years and is characterized by the co-existence of inflammation and repair mechanisms. It often occurs in cases where the injurious factor cannot be readily removed by the host or, in the case of autoimmune disease, is an aberrant immune response to thehost itself. Several features are characteristic of both acute and chronic inflammation.

Increased local blood flow

An increase in local blood flow serves to facilitate the delivery of soluble andcellular mediators to the site of inflammation and is largely due to vasodilation caused by nitric oxide (NO) andvasodilating prostaglandins. Activation of nitric oxide synthase (NOS) in endothelial cells (eNOS) and leukocytes(iNOS) facilitates the production of NO. Prostaglandins are produced from cell membrane-derived arachadonic acidthrough the action of the enzyme cyclooxygenase. Clinically, increased blood flow is manifested as redness andwarmth at the site of inflammation.

Increased vascular permeability

Increased vascular permeability results from endothelial cell retraction andthe development of transcytoplasmic endothelial cell pores as well as by direct injury caused by trauma or toxicleukocyte products. This response occurs primarily in post-capillary venules and results in the exudation of proteinrich fluid from the vascular compartment into the interstitium. The purpose of the exudative response is to deliver soluble mediators such as antibodies and acute phase proteins to the site of injury. The increase in vascular permeability is mediated by several factors including histamine, bradykinin, platelet activating factor (PAF),substance P, and leukotrienes. Edema and swelling are signs of increased vascular permeability duringinflammation.

Leukocyte migration

The exudation of protein rich fluid from the vascular compartment results inhemoconcentration and stasis at the site of injury. This process facilitates the movement of leukocytes to theendothelial surface of capillaries and venules, a process called margination. Activation of endothelial cells by pro-inflammatory cytokines induces expression of cell surface proteins called selectins that cause low affinity binding of leukocytes to the endothelial surface. This process keeps leukocytes in close proximity to the endothelium, a processknown as rolling. Continued cytokine production further stimulates endothelial cells to express high affinityadhesion molecules such as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1). Concurrently, leukocytes are induced to express cell surface integrins. The endothelial ICAMs andleukocyte integrins form high affinity bonds that latch the leukocytes to the endothelial surface. The boundleukocytes subsequently migrate between the endothelial cells and travel to the site of injury. Chemoattractantcytokines (chemokines), bacterial products and complement components mediate the homing of leukocytes to thesite of inflammation. Neutrophil infiltration is a hallmark of acute inflammation whereas the presence of mononuclear cells such as lymphocytes and monocytes is typical of chronic inflammation. The migration of specificleukocyte populations is largely regulated by chemokines that specifically promote migration of individual celltypes.The inflammatory response is tightly controlled and usually functions effectively to limit infection or injuryand promote tissue repair. Normally, a balance exists among pro-inflammatory cytokines such as TNF

, IL-1, IL-12 and IFN-

and anti-inflammatory signals provided by IL-10, transforming growth factor

and certain prostaglandins. This balance results in effective activation and subsequent resolution of the inflammatory response.However, in cases where the pro-inflammatory response predominates, severe systemic inflammation may ensue astypified by sepsis and the systemic inflammatory response syndrome [1]. Conversely, predominance of the anti-inflammatory response may cause a state of relative immunosuppression to develop. This phenomenon often resultsafter major trauma, thermal injury or in the post-septic state. Patients exhibiting post-inflammatoryimmunosuppression may be more susceptible to infectious complications.

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Innate and acquired immunity.

The immune response to tissue injury or infection can be divided into innateand acquired responses. The innate immune system mounts the initial response; it exists prior to encounter withmicrobes or injury and is rapidly activated. The previously discussed phases of vasodilation, increased vascular permeability and cellular infiltration are part of the innate immune response. The primary cellular components of theinnate immune system are macrophages, dendritic cells, natural killer (NK) cells and neutrophils . In addition tothese cellular components, circulating effector proteins such as complement, acute phase reactants and thecoagulation cascade play important roles in innate immunity. The activity of cytokines and non-cytokine mediatorsof inflammation largely determine the magnitude of the innate response.The acquired immune response is induced primarily by presentation of foreign antigens to CD4

and CD8

Tcells by the class II and class I major histocompatability complexes (MHC), respectively. Prior exposure of naïve Tcells by antigens induces cellular proliferation and generation of memory T cells that respond more rapidly upon re-exposure to the initial antigen. CD4

T cell activation causes cytokine production and amplifies the innate andacquired immune systems. The specific cytokines produced by CD4

T cells is dependent on the immunologicalmicroenvironment at the time of antigen presentation. The best-defined subsets of CD4

T cells are T helper 1 (Th1)and T helper 2 (Th2) cells. Th1 cells are induced by microbial infection or exposure to microbial products thatstimulate secretion of the cytokine IL-12 by macrophages. Antigen presentation to T cells in the presence of IL-12induces Th1 cell differentiation and the production of interferon gamma (IFN

). IFN

amplifies the acuteinflammatory response, particularly by activation of macrophages, to enhance pro-inflammatory cytokine secretion, phagocytosis and respiratory burst activity. The principal function of Th1 cells is promotion of phagocyte-mediateddefense against infections. Th2 cells are induced by chronic exposure of T cells to helminthes and environmentalantigens in the absence of IL-12. This results in the differentiation of Th cells that preferentially secrete IL-4, IL-5and IL-13. Th2 cells potentiate IgE and eosinophil/mast cell-mediated immune responses such as allergies and thereaction to certain parasitic infections. CD8

T cells respond to antigens presented in conjunction with class I MHCthat is expressed by all nucleated cells. These interactions allow us to distinguish “self” from “non-self “ and torecognize cells that are infected with viruses.

Cytokine and Non-Cytokine Mediators of Inflammation.

Cytokines.

Cytokines comprise a broad group of polypetides with varied functions within the immune system.Several cytokines including IFN

, IL-4, IL-12 and IL-13 are discussed above. However, several cytokines play animportant role in regulating the pro-inflammatory response. The classical mediator of systemic inflammation istumor necrosis factor

(TNF

). TNF

is released primarily by macrophages and monocytes within minutes of localor systemic injury and modulates a variety of immunologic and metabolic events. It is a potent activator of neutrophils and mononuclear phagocytes and also serves as a growth factor for fibroblasts and as an angiogenesisfactor. Systemic release of TNF

induces numerous physiological effects that typify systemic inflammationincluding fever, cachexia, secretion of acute phase proteins by the liver, activation of the coagulation cascade, production of systemic vasodilators such as NO, and alterations in glucose metabolism. Numerous studies haveshown that administration of TNF

to experimental animals will mimic the systemic inflammatory responseobserved in sepsis. TNF

can also induce apoptosis or programmed cell death through interaction with the TNFreceptor I subtype.The physiological effects of IL-1 are essentially identical to those of TNF

. However, IL-1 does not inducetissue injury or apoptosis by itself but can potentiate the injurious effects of TNF

. The IL-1 family of proteins,including IL-18, are the only group of cytokines for which known natural antagonists have been identified. The IL-1receptor antagonists bind to the IL-1 receptor but do not induce receptor activation. These proteins appear tofunction as competitive inhibitors of IL-1 action.Interleukin-6 (IL-6), produced by macrophages, endothelial cells and fibroblasts, is commonly increased in thecirculation of patients with systemic inflammation. The primary effect of IL-6 is to induce secretion of acute phase proteins from the liver as well as serve as a growth and differentiation factor for B-lymphocytes. Although IL-6 doesnot appear to directly mediate tissue injury, persistent elevation of plasma IL-6 levels has been shown to correlatewith poor outcome in critically ill patients. In this regard, IL-6 may serve as a marker of ongoing inflammation.Anti-inflammatory cytokines play a key role in regulating the pro-inflammatory response. Among the mostwell understood anti-inflammatory cytokines are IL-10 and TGF

. Macrophages and T cells are the primary sourcesof IL-10. Its function is to inhibit macrophage production of IL-12 and expression of surface molecules such as classII MHC and B7 proteins that are important for antigen presentation to T lymphocytes. The importance of IL-10 inregulating the inflammatory response is clearly shown by IL-10 knockout mice that develop inflammatory boweldisease and are exquisitely sensitive to pro-inflammatory stimuli such as endotoxin or bacterial challenge. TGF

316Page 3 produced by a variety of cell types including T cells and monocytes. It acts to inhibit T cell proliferation andmacrophage activation. TGF

knockout mice develop a lethal auto-inflammatory syndrome shortly after birth.

Chemokines.

Chemokines are a family of proteins that function primarily as chemotactic factors for leucocytes. IL-8 is a potent chemoattractant for neutrophils and is a major factor in recruiting neutrophils toinflammatory foci during acute inflammation. Other cytokines serve as specific chemoattractants for lymphocytes,monocytes, dendritic cells and eosinophils.

Non-cytokine mediators of inflammation.

Platelet activating factor (PAF) is a phospholipid autocoid released by endothelial cells that regulates the release of cytokines and amplifies the pro-inflammatory response. It appears to be an important factor in the adhesion of neutrophils to endothelial cells. Eicosanoids are arachadonic acidmetabolites that regulate many aspects of the immune response. Leukotrienes (LTC

-LTE

) induce contraction of endothelial cells and encourage capillary leakage. Thromboxane A

, a macrophage and platelet-derived factor, promotes platelet aggregation, vasoconstriction and, potentially, tissue thrombosis. Vasodilatory prostaglandins suchas PGE

cause vasodilation.

The coagulation cascade.

Pro-inflammatory cytokines, microbes and tissue injury stimulate tissue factor expression by macrophages and endothelial cells. Tissue factor promotes thrombin formation and clotting primarily by activation of the extrinsic pathway. In addition, inflammatory mediators stimulate production of plasminogenactivator inhibitor 1 (PAI-1) which suppresses fibrinolysis and promotes clot retention. Thrombin amplifiesinflammatory mechanisms by stimulating pro-inflammatory cytokine production by monocytes, macrophages andendothelial cells. These interactions potentiate both the inflammatory and coagulation cascades following tissueinjury. Mechanisms normally function to inhibit over-activation of the clotting cascade. One mechanism is production of activated protein C [2]. Activated protein C inhibits the coagulation cascade by causing degradation of activated factors V and VIII. It also reduces production of pro-inflammatory cytokines by activated leukocytes.Therefore, activated protein C inhibits both procoagulant and pro-inflammatory pathways.

Complement.

The complement cascade is comprised of more than 30 proteins that interact in a complexfashion to mediate inflammation and lysis of microbes and other cells. Products of the complement cascade, mostnotably C3a and C5a, are potent activators of inflammation and leukocyte chemotaxis. C3a and C5a also directlyactivate neutrophils and promote release of reactive oxygen intermediates and proteases. The membrane attack complex (MAC) is the terminal component of the complement cascade. MAC results from the aggregation of thecomplement components C5-C9 on biological membranes. The accumulation of MAC on cell surfaces causesdisruption of target cell membranes.

Sepsis and the Systemic Inflammatory Response Syndrome (SIRS).

Sepsis is a common cause of morbidity and mortality for critically ill patients with more than 650,000 casesreported in the United States in the year 2001 [3]. The care of septic patients is estimated to inflict an estimated costof $17 billion on the health care system in the United States. Furthermore, the number of patients with sepsis isincreasing. Major trauma is another major public health problem in the United States and the leading cause of deathamong persons less than 35 years of age [4]. Systemic inflammation contributes significantly to trauma- and sepsis-associated pathophysiology. Therefore, much interest has been generated in defining the physiological ramificationsof systemic inflammation.The phrase systemic inflammatory response syndrome (SIRS) was recommended by the American Collegeof Chest Physicians/Society for Critical Care Medicine (ACCP/SCCM) consensus conference in 1992 to describe asystemic inflammatory process, independent of its cause [5]. The proposal was based on clinical and experimentalresults indicating that a variety of conditions, both infectious and non-infectious (

i.e.

burns, ischemia-reperfusioninjury, multiple trauma, pancreatitis, systemic infection), induce a similar host response. Two or more of thefollowing conditions must be fulfilled for the diagnosis of SIRS or sepsis to be made: (1) body temperature > 38

Cor < 36

C; (2) heart rate > 90 beats/min., (3) respiratory rate > 20 /min. or PaCO2< 32 mmHg, (4) leukocyte count>12000/µL, < 4000/µL, or >10% immature (band) forms, all occurring as an acute alteration from baseline in theabsence of other known causes for the abnormalities. Most of the SIRS criteria are also addressed in other scoringsystems of injury-induced physiologic derangement such as the Acute Physiology and Chronic Health Evaluation(APACHE), Mortality Probability Model (MPM) and Simplified Acute Physiology Severity (SAPS) systems.Several investigators have criticized the definition of SIRS as being too sensitive, non-specific and encompassingthe majority of ICU patients and certainly the vast majority of patients suffering major trauma [6]. The categories of severe sepsis and septic shock were also included to define the continuum of this disease process. Severe sepsisincluded the additional derangements of organ dysfunction, hypotension and hypoperfusion. Evidence of hypoperfusion included, but was not limited to, lactic acidosis, oliguria and altered mental status. Septic shock, themost severe form of sepsis, was characterized by hypotension and hypoperfusion requiring the use of inotropes/pressors in patients that were adequately volume resuscitated. In an effort to define a continuum of

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