Local Anesthetics and the Inflammatory Response

LOCAL anesthetics (LA) are known for their ability to block Na+channels. However, they have significant effects in several settings other than local and regional anesthesia or antiarrhythmic treatment, the areas in which they are used traditionally. These effects result from LAs interacting with other cellular systems as well. Interestingly, some of these effects occur at concentrations much lower than those required for Na+channel blockade. For example, whereas the half-maximal inhibitory concentration (IC50) of lidocaine at the neuronal Na+channel is approximately 50–100 μm (depending on the specific channel subtype and study preparation), 1the compound inhibits signaling through m1 muscarinic receptors (expressed recombinantly in Xenopus laevis oocytes) with an IC50of 20 nm, that is, 1,000- to 5,000-fold lower. 2This sensitivity of other targets has two important consequences. First, we assume that LAs, at concentrations that result in significant Na+channel blockade, also affect a number of other systems. Second, relatively low LA concentrations (such as attained in blood during epidural anesthesia or analgesia or during intravenous LA infusion) that block neuronal Na+channels to a limited extent only still can have significant pharmacologic effects. We suggest that some of these "alternative actions" may be beneficial in the clinical setting, and others may be responsible for some adverse effects of LAs. Although Butterworth and Strichartz 3a decade ago urged investigation of such actions and their mechanisms, much remains to be discovered. To demonstrate the variety of LA effects, table 1provides an overview of various LA actions reported in the literature. This review focuses on an area in which alternative actions of LAs show much promise for clinical application: their effects on the inflammatory response and especially on inflammatory cells (mainly polymorphonuclear granulocytes [PMNs] but also macrophages and monocytes). PMNs do not express Na channels, 4and LA effects on these cells therefore are not caused by Na channel blockade. LA effects on these cells are not affected by Na channel blockers such as tetrodotoxin or veratridine. 5Overactive inflammatory responses that destroy rather than protect are critical in the development of a number of perioperative disease states, such as postoperative pain, 6–8adult respiratory distress syndrome (ARDS), 9–11systemic inflammatory response syndrome, and multiorgan failure. 12–15Perioperative modulation of such responses is therefore relevant to the practice of anesthesiology, and LAs may play significant roles in this regard.In general terms, inflammation can be described as a reaction of the host against injurious events such as tissue trauma or presence of pathogens. Release of vasoactive mediators from tissue mast cells (histamine, leukotrienes), as well as from platelets and plasma components (bradykinin), causes vasodilation and increased vascular permeability, leading to the classic inflammatory signs of redness (rubor ) and heat (calor ). The resulting edema causes swelling (tumor ), and interactions of inflammatory mediators with the sensory systems induce pain (dolor ). Significant local inflammation causes a systemic response, termed the acute phase reaction . This response is manifested by increases in acute phase proteins (C-reactive protein, complement factor C3, fibrinogen, and serum albumin), followed by activation of several systems of mediators (kinin system, complement system, lipid mediators, and cytokines). Cytokines, in particular, are important for regulation of the inflammatory response. The local release of cytokines (interleukin-1 [IL-1], IL-8, tumor necrosis factor [TNF]) coordinates the inflammatory response at the site of injury and induces neutrophil chemotaxis to the site of inflammation. Some cytokines (IL-1, IL-6, TNF) released from inflammatory sites mediate the systemic response. They induce fever and the acute phase reaction, mobilize neutrophils from the bone marrow, and promote lymphocyte proliferation.The inflammatory response induces cells (primarily PMNs and monocytes) to migrate into the affected area, in which they destroy pathogens, largely by phagocytosis. This process can be divided into several stages (fig. 1):The inflammatory response is essential for structural and functional repair of injured tissue. It is, however, a double-edged sword. Excessive generation of proinflammatory signals, as occurs in several disease states, can aggravate tissue damage because of products derived from inflammatory cells. This suggests that modulation of the inflammatory response (e.g. , by LAs) might prevent such tissue damage.This section describes some actions of LAs on inflammatory processes. We focus on three specific disease states relevant to anesthesiologists: inflammatory lung injury, increased microvascular permeability, and myocardial ischemia–reperfusion injury. In addition, we discuss briefly the use of LAs to treat inflammatory bowel disease, an area of active clinical investigation. Finally, we refer to an issue of considerable importance: the possibility that LAs, because of their antiinflammatory properties, might increase the risk of infection in certain settings.High LA concentrations have been used in some studies, and, in order to judge the clinical relevance of the various reports, it is important to consider the concentrations of LAs used in clinical practice. These concentrations differ widely, depending on the method of application. In order to achieve systemic effects after intravenous administration of LAs, plasma levels in the low micromolar range are required (for lidocaine, approximately 0.5–5.0 μg/ml, corresponding to 2–20 μm);16For example, intravenous administration of lidocaine at 2–4 mg/min leads to plasma concentrations of 1–3 μg/ml (4–12 μm) after 150 min. 17After 15 min a 2 mg/kg intravenous bolus of lidocaine results in peak plasma levels of 1.5–1.9 μg/ml (6–8 μm). 18Similar plasma concentrations are obtained after epidural administration 19or topical application of LAs (1 mg/cm2) in partial-thickness burns 20; LAs applied topically on intact skin are likely to achieve substantially lower plasma concentrations. Plasma concentrations of lidocaine above 10 μg/ml tend to produce adverse effects. 21In contrast, after local application or tissue infiltration of these drugs, LA tissue concentrations are typically in the millimolar range. Similar concentrations are present around the spinal nerves after epidural or spinal administration of LAs. 22LA concentrations at specific sites vary widely, depending on the method of administration. In vivo , LAs are largely protein-bound, lowering the concentrations available for interactions with signaling systems.Most studies have used lidocaine as a prototypical compound. Although other LAs appear to exhibit largely similar actions, there is clearly a lack of comparative studies with LAs from various classes, and very few structure–function studies have been performed. Data obtained with lidocaine cannot necessarily be extrapolated to other LAs.Polymorphonuclear granulocytes, macrophages, and cytokines play crucial roles in the pathogenesis of inflammatory lung injury. Cytokines increase the expression of adhesion molecules, thereby increasing margination of PMN accumulated in the lung. The attachment of PMN affects endothelial cells and microvascular permeability.Nishina et al. 23reported that pre- or early posttreatment with lidocaine (bolus 2 mg/kg + 2 mg · kg−1· h−1continuous infusion, yielding plasma concentrations of 1.2–2.5 μg/ml [5–10 μm]) attenuates the late phase of acid installation–induced lung injury in rabbits. Lidocaine decreased PMN accumulation in the lung. Superoxide anion production by PMNs obtained from the pulmonary artery was inhibited, indicating reduced free radical generation. In turn, this would reduce endothelial damage and therefore might decrease pulmonary edema. The HCl-induced increase in pulmonary wet:dry ratio and albumin extravasation was attenuated in lidocaine-treated rabbits, and cytokine levels in bronchoalveolar fluid decreased. (Fluid used for bronchoalveolar lavage routinely contains high concentrations of LA in clinical 24and animal experiments. 25These concentrations of LA have been shown to affect the behavior of alveolar macrophages significantly. 26) The decrease in cytokines was more likely a result from attenuation of the inflammatory response, rather than direct suppression of cytokine production by macrophages or alveolar epi- and endothelium. Plasma levels of IL-6 and IL-8, and IL-6 concentrations in bronchoalveolar fluid, were less in lidocaine-treated animals. The antiinflammatory effects of lidocaine improved lung function after tracheal HCl installation, indicated by improved partial pressure of oxygen and attenuation of both decreased compliance and increased resistance. The protective effects observed were likely a result of inhibition of sequestration and activation of PMNs. 23Interactions of PMNs with endothelial cells also may be important in the pathogenesis of organ dysfunction induced by endotoxin. Increased margination of activated PMN in response to an inflammatory stimulus contributes to endothelial damage. Because LAs interfere with the initial steps of inflammation in vitro , a protective effect of these drugs in endotoxin-induced lung injury might be expected. Schmidt et al. 27reported that, in a rat model of sepsis, pretreatment with lidocaine (plasma concentration 1.4–2.5 μg/ml [6–10 μm]) attenuated endotoxin-induced increases in PMN adherence, PMN activation and migration to the inflammatory site, and PMN metabolic function, as assessed by an inhibition of free radical production. The protective action of lidocaine was not a result of differences in venular wall shear rate. Instead, inhibition of PMN adherence to endothelial cells, PMN function, and suppression of histamine release by lidocaine may explain the observed decrease of microvascular permeability in lidocaine-pretreated rats. Similar results were obtained by Mikawa et al., 28who showed that pretreatment with lidocaine (single dose of 2 mg/kg intravenously followed by continuous infusion of 2 mg · kg−1· h−1) significantly attenuates endotoxin-induced lung injury in rabbits, by attenuating the accumulation and the O2−production of PMNs.The mechanisms underlying ARDS induced by long-term exposure to high oxygen concentrations remain unclear. An inflammatory mechanism, including PMN activation and sequestration in the lung, may be pivotal in the pathogenesis of this syndrome. This hypothesis is confirmed by the fact that antioxidants protect the lung in such situations. Considering the effects of LAs on inflammatory cells, it would be expected that their antiinflammatory properties help prevent hyperoxic lung injury. Takao et al. 29demonstrated a protective effect of LAs on inflammatory responses and pulmonary function in a rabbit model of hyperoxia-induced lung injury. Lidocaine infusion to systemically relevant plasma concentrations (1.4–2.5 μg/ml [6–10 μm]) decreased chemotactic factors (C3a, C5a, TNF-α, IL-1β) in bronchoalveolar lavage fluid and resulted in less PMN accumulation than in saline-infused rabbits. PMN from lidocaine-treated rabbits showed a marked reduction in chemiluminescence, indicating reduced free radical release and therefore less likelihood of endothelial damage. The treated animals developed less lung edema, as demonstrated by a decrease in albumin extravasation and improved wet:dry ratio of the lung. Lidocaine infusion was associated with fewer histopathologic changes of lung damage.LAs have been shown to be protective in various animal models of ARDS, and the underlying mechanism appears to be their antiinflammatory action.Increased microvascular permeability is common in many inflammatory diseases. Examples relevant to anesthesiologists include ARDS, sepsis, burns, and peritonitis. Various studies have shown protective effects of LAs on this process.In an in vivo model of ligature-induced obstructive ileus in rats, lidocaine, administered intravenously (2 mg/kg) or sprayed directly onto the serosa, suppressed the inflammatory reaction, as indicated by marked inhibition of fluid secretion and albumin extravasation. 30Although blockade of neurons in the enteric nervous system (especially the myenteric plexus), with subsequent reduction in the release of secretory mediators such as vasoactive intestinal polypeptide, may have contributed to the antisecretory action of lidocaine, this does not explain easily why lidocaine pretreatment of the serosa of the obstructed jejunum reduced the inflammatory reaction in the bowel wall even 18 h later. Lidocaine's interference with several steps of the inflammation cascade may be a more likely explanation for the protective effect observed in this study. 31Similar results were obtained by Rimbäck et al. 30They studied the effects on HCl-induced peritonitis of topical pre- and posttreatment of the peritoneal surface with lidocaine (37 mm) and bupivacaine (17.5 mm). Both anesthetics significantly inhibited Evans blue albumin extravasation, a marker of microvascular permeability. Although both drugs were titrated to the same nonionized fraction (based on pKa), lidocaine showed a more potent inhibitory effect. 30Using hamster cheek pouch, Martinsson et al. 32observed reversible inhibition by ropivacaine (100 μm) of LTB4-induced plasma exudation, indicating that the effect is not specific to lidocaine.Thermal injury activates the complement system and other inflammatory cascades, resulting in progressive plasma extravasation with subsequent hypoproteinemia and hypovolemia. Antiinflammatory drugs inhibit burn-induced albumin extravasation, 33,34suggesting a role for inflammatory mediators in the pathogenesis of edema. Therefore investigators were interested in studying whether the anti-inflammatory properties of LAs could protect microvascular integrity, without increasing infection rate. Using skin burns in rats, Cassuto et al. 35reported that topical application or systemic administration of amide LAs, in doses resulting in plasma concentrations below toxic level, 17,20significantly inhibited plasma exudation in rats compared with placebo. This protective action could be explained by several of the known effects of LAs. Inhibition of PMN delivery to the site of inflammation, 36direct suppression of PMN-endothelial adhesiveness, 37reduced generation of toxic oxygen metabolites, 38,39impaired prostaglandin and leukotriene production 33,40or increased local prostacyclin production, 41and reduced PMN stickiness and adherence to injured endothelium all may contribute to the reduced plasma extravasation. These findings were not confirmed, however, by Nishina et al. , 23who did not find that LAs affect leukotrienes and prostacyclin. Inhibition of sensory neurons with resultant decreases in release of substance P, suggested to be important for edema development after thermal injury, 42is another possible explanation. Cassuto et al. 35reported that the protective effect was lost if the systemically administered concentration of lidocaine was increased from 10 to 30 μg · kg−1· min−1. A potential explanation for this unusual concentration-dependency is activation or block of additional pathways at the higher lidocaine concentration. A similar and possibly related phenomenon is the concentration-dependent action of LAs on vascular smooth muscle in vitro and in vivo :43Low concentrations (for lidocaine 1 μg/ml–1 mg/ml, corresponding to 4 μm–4 mm) induce vasoconstriction; greater concentrations induce vasodilation. It is conceivable that vasoconstriction would decrease edema formation, and vasodilation would enhance it.Inhibiting the inflammatory response could increase the incidence of infection, but Brofeldt et al. 20reported that 5% lidocaine cream, applied to the skin of patients with partial-thickness burns in concentrations up to 2.25 mg/cm2, was associated with good pain relief, plasma concentrations below toxic levels, no infections or allergic complications, and excellent wound healing. These studies suggest that benefit may be obtained from topical treatment with LAs, even in patients with extensive burns.Inflammatory processes contribute to the development of several bowel diseases. Ulcerative colitis and proctitis are caused by both immunologic and inflammatory stimuli. In a rat colitis model, ropivacaine showed protective effects, 32,44and clinical studies have shown that LAs can be effective against the severe mucosal inflammation of these diseases. 45,46Arlander et al. 47reported that patients with ulcerative colitis treated rectally with ropivacaine 200 mg twice daily (mean peak plasma concentrations 1.0–1.4 μg/ml [3.6–5.0 μm]) demonstrated decreased inflammation and reduced clinical symptoms after only 2 weeks of treatment. Perturbation of the link between inflammatory and immunocompetent cells, as well as blockade of hyperreactive autonomic nerves (which also may play a causative role in these diseases), 48were suggested as possible explanations for the LA effect. Decreased release of proinflammatory lipoxygenase products (LTB4or 5-hydroxy-eicosatetraenoic acid), with other potentially cytoprotective eicosanoids (15-hydroxy-eicosatetraenoic acid and prostacyclin) unaffected, also may contribute to this beneficial effect of ropivacaine. 49Lidocaine failed, however, to inhibit prostanoid release by human gastric mucosa in vitro at concentrations less than 250 μg/ml. 50Lidocaine (plasma concentration 5–15 μm) accelerated the return of bowel function in patients undergoing radical prostatectomy, 51resulting in a significant shortening of hospital stay. LAs (lidocaine 100 mg bolus intravenously + 3 mg/min continuous intravenous infusion, or bupivacaine 2 mg/kg intraabdominal installation) also shortened the duration of postoperative ileus in patients undergoing major abdominal surgery. 52,53Peritoneal surgery is associated with release of inflammatory mediators such as histamine, prostaglandins, and kinins. 52,54Activation of abdominal reflexes resulting in longlasting inhibition of colonic motility after surgery is likely to be a result of inflammatory reactions in the area undergoing surgery. Because LAs affect the release of inflammatory agents, beneficial effects on bowel function may result at least in part from lidocaine's antiinflammatory effects. This hypothesis is supported by the observation that nonsteroidal antiinflammatory drugs are also effective. 55The antiinflammatory effect of LAs is prolonged and persists after serum levels have decreased. 45,56This might explain lidocaine's effect on bowel function 36 h after infusion was discontinued. 52Taken together, these findings show significant promise for the use of LAs in the treatment of inflammatory bowel disease, as well as in the attenuation of postoperative ileus.Acute myocardial infarction is not usually considered an inflammatory disease, but infarction, and particularly ischemia–reperfusion injury, is accompanied by a significant cardiac inflammatory response. PMN-endothelial interactions occurring during myocardial ischemia and reperfusion are thought to play a crucial role, and PMN-derived oxygen metabolites are important in myocardial injury associated with reperfusion of the ischemic heart. 57Activated PMN can induce structural changes in the heart through the action of free radicals and arachidonic acid metabolites. 58In 1984 Mullane et al. 59reported that drugs that impair PMN function may reduce infarct size. Recent studies have shown that IL-6 and IL-8 are important regulators of the inflammatory response in myocardial infarction, 60and C5a is suggested as a key mediator of tissue injury in this setting. 61Moreover, expression of PMN and monocyte adhesion molecules and their ligands increases in the acute phase of myocardial infarction. 62It is not surprising that blockade of adhesion molecules, reducing PMN accumulation in the myocardium, exerts significant protective effects on myocardial ischemia–reperfusion injury in rats. 63Intravenous administration of antibodies against CD11b-CD18 reduced myocardial reperfusion injury in an animal model. 64Similar findings were observed after treatment with 17β-estradiol, which decreased TNF-α levels and reduced intercellular adhesion molecule-1–mediated binding of PMN to injured myocardium, leading to less PMN accumulation and subsequent protection against reperfusion injury. 65Leukotriene synthesis inhibitors also provide significant cardioprotection in myocardial ischemia. 66PMN-mediated endothelial reperfusion injury can be attenuated by PMN depletion during reperfusion. 67Experiments in a porcine model of myocardial ischemia have shown that lidocaine, either administered intravenously or perfused in a retrograde manner before onset of reperfusion, preserved the ischemic myocardium and reduced infarct size after reperfusion. 68Lidocaine infusions in dogs reduced infarct size, possibly by inhibiting release of toxic oxygen metabolites. 69In contrast, de Lorgeril et al. 70reported that, in their dog model, lidocaine (plasma concentration 13 μm) reduced neither infarct size nor myocardial PMN accumulation significantly. These discrepancies might be caused by differences between the models, particularly the duration of occlusion.Lidocaine is used for antiarrhythmic treatment after myocardial infarction. It is conceivable that part of the antiarrhythmic effect in this setting is a result of antiinflammatory effects of lidocaine in areas of myocardial infarction. Although lidocaine administration failed to be effective in treating reperfusion arrhythmias in several experimental studies in dogs and pigs, 70,71lidocaine decreased reperfusion arrhythmias caused by free radical–induced enhanced automaticity, without effect on reentry arrhythmias. 72An important aspect of the antiinflammatory properties of LAs is a possible increase in susceptibility to infections: LA-mediated depression of the PMN oxidative metabolic response may decrease the ability to control bacterial proliferation. Investigations suggest, however, that the remaining PMN function is sufficient to minimize the risk. Peck et al. 38found that the microbicidal function of PMNs from patients receiving lidocaine infusions was only slightly decreased. Although Groudine et al. , 51who showed that lidocaine infusion has beneficial effects on bowel function in patients undergoing radical prostatectomy, concluded that lidocaine might be useful in major abdominal surgery, caution seems warranted in employing LA infusions (intravenously or epidurally) in surgical patients with gross bacterial contamination of body cavities. In a letter responding to the report of Groudine et al. , Drage 73referred to a study by MacGregor et al. , 36in which five of six rats treated with lidocaine (1.5 mg/kg intravenous bolus + 0.3 mg · kg−1· min−1) died within 48 h from Staphylococcus aureus inoculation (3 × 108colony-forming units intraperitoneally), but of six rats that were inoculated with S. aureus but not treated with lidocaine only a single animal died. Powell et al. 74reported increased infection risk if eutectic mixture of local anesthestics cream was applied to contaminated wounds.It appears, therefore, that LAs are most likely to be beneficial in settings of sterile inflammation, in which the excessive inflammatory response is a major pathogenic factor. In contrast, LAs might be detrimental in settings of bacterial contamination, in which an unmitigated inflammatory response is required to eliminate the microorganisms.Local anesthetics, in millimolar concentrations, possess antimicrobial properties in vitro 75,76and in vivo . 77Lidocaine (37 mm) inhibits growth of Escherichia coli and Streptococcus pneumoniae but has no effect on S. aureus or Pseudomonas aeruginosa ; 2% lidocaine (74 mm) inhibits all of these bacteria. 78Schmidt and Rosenkranz, 79utilizing a larger number of bacterial pathogens, showed similar results, demonstrating inhibition of all pathogens except S. aureus and P. aeruginosa .The mechanisms behind this antibacterial action are unclear. 80Recent investigations suggest that the antimicrobial activity seems to be bactericidal rather than bacteriostatic. 81Recently, Sakuragi et al. 82showed that preservative-free bupivacaine (4.4–26.0 mm) possesses temperature- and concentration-dependent bactericidal activity against microorganisms in the human skin flora. S. aureus was more resistant to bactericidal activity of bupivacaine than were Staphylococcus epidermidis or E. coli. Such antibacterial actions, however, are obtained only at high concentrations. Feldman et al. 83observed that low concentrations of bupivacaine had, at best, limited antibacterial activity and did not inhibit growth of coagulase-negative staphylococcus. They concluded that LAs are unlikely to prevent, for example, epidural catheter–related infections. Only bupivacaine concentrations of 8 mm or higher appeared to have antibacterial properties. Concentrations of LAs in the epidural environment, are in the millimolar range. Although, to our knowledge, no published studies exist, it might be possible that the antibacterial properties of epidural LAs contribute to prevention of epidural infections; if so, eliminating LAs from epidural infusions might result in a higher infection rate.High concentrations of LAs also inhibit viruses. Using an in vitro test (plaque neutralization test in Vero cells) to study the antiviral action of LAs against herpes simplex virus 1, De Amici et al. 84reported that anesthetics with intermediate potency such as mepivacaine can inhibit viral replication by up to 50%, but only with concentrated solutions (more than 1%[35 mm]) and if applied in combination with epinephrine. Bupivacaine (15.5 mm) also inhibited, but again, without epinephrine the effect was reduced markedly. Inhibition was maximal with 1% (approximately 31-mm) solutions. It is likely that the inhibitory effect is directed primarily against the virus itself and not (as with most antiviral drugs) mediated by interference with the mechanisms of cellular replication. LAs can exert antiviral activity in a concentration-dependent manner. This effect is influenced by other factors such as osmolarity and presence of epinephrine (possibly a p H effect), especially if a less concentrated solution is employed.Because the antibacterial and antiviral effects of LAs are observed only at high concentrations, antiinflammatory actions of these compounds at systemic levels in theory can increase the risk of infection. This has not been relevant in the in vivo studies reported to date, except in settings of gross bacterial contamination. One of the hallmarks of the findings described here is that these compounds can modulate excessive inflammatory responses without significant impairment of host defenses. The next section describes the cellular actions underlying this inflammatory modulation.Leukotrienes, particularly LTB4, play an important role in the early phase of inflammation. 85Reduction of leukotriene release is therefore a major option for modulating inflammation.Leukotriene B4, formed in inflammatory cells such as PMNs and monocytes, is a potent stimulator of PMN activity. It induces margination at endothelial cells, degranulation, diapedesis, and superoxide generation and acts synergistically with prostaglandin E2to enhance vascular permeability. It has a high chemotactic potency for PMNs (i.e. , it is a potent leukoattractant) in vitro and in vivo . Blocking release of this chemotactic mediator exerts an antiinflammatory action, because PMNs no longer are recruited to the inflammatory site. LAs block leukotriene release. In vitro preincubation of human PMNs or monocytes with different concentrations of lidocaine or bupivacaine (2–20 mm lidocaine and 0.4–4.4 mm bupivacaine) inhibit LTB4release nearly completely. 86This may explain some of the antiinflammatory effects of the compounds. Because LTB4, in combination with prostaglandin E2, induces edema formation, blockade of LTB4release by LAs may explain in part the beneficial effects of LAs on edema formation. 30Interleukin-1α is another inflammatory mediator, which, acting on its receptor on PMNs, stimulates phagocytosis, respiratory burst, chemotaxis, and degranulation. Reduced release of cytokines such as IL-1α therefore also would contribute to an antiinflammatory effect of LAs. In vitro , amide LAs, such as lidocaine and bupivacaine, dose-dependently (lidocaine 0.2–20.0 mm, bupivacaine 44–4,400 μm) inhibit IL-1α release in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. 86Lidocaine also inhibits histamine release from human peripheral leukocytes, cultured human basophils, and mast cells in vitro at concentrations in the high micromolar range. 87It therefore appears that LAs can inhibit the release of several critical inflammatory mediators; in addition to direct effects on PMNs and macrophage function, this may be one of the main pathways by which they exert their antiinflammatory effects.Adhesion of PMNs to endothelium, if excessive, may induce endothelial injury, which is mediated by several adhesion molecules. One of the most important for firm adhesion of PMN to endothelium and subsequent transmigration (diapedesis) is CD11b-CD18, a member of the integrin family. 88This receptor is expressed constitutively on the surface of nonactivated PMN, but expression increases markedly after inflammatory stimulation. Binding of activated PMN to endothelial cells by CD11b-CD18 increases intracellular peroxide levels in the endothelial cells, in which reactive oxygen species can have detrimental effects. 89Monoclonal antibodies against CD11b-CD18 protect in vitro against endothelial cel