anti-inflammatory cytokines, including IL-10 and IL-11. Activation of the extrinsic clotting pathway by tissue factor and inhibition of fibrinolysis b

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1 DRUG THERAPY REVIEW FOR ARDS Pharmacological Therapy for Acute Respiratory Distress Syndrome RAKSHA JAIN, MD, AND ANTHONY DALNOGARE, MD Acute respiratory distress syndrome (ARDS) is an inflammatory process caused by a variety of direct and indirect injuries to the lungs. Despite improvements in supportive care and advances in ventilator management, mortality in patients with ARDS remains high. Multiple pharmacological interventions have been investigated but have not shown improved survival. Clinical trials using corticosteroids, prostaglandins, nitric oxide, prostacyclin, surfactant, lisofylline, ketoconazole, N-acetylcysteine, and fish oil have been unable to show a statistically significant improvement in patient mortality. As more is understood about the pathophysiology of ARDS, treatment strategies such as increasing alveolar fluid clearance through activation of sodium channels, enhancing repair of alveolar epithelium with growth factors, inhibiting fibrin deposition, blocking proinflammatory transcription factors, preventing the effect of potent vasocontrictors such as endothelin, and using antibodies against key inflammatory cytokines are being explored. This review focuses on the pharmacological treatments studied clinically, proposed reasons for their lack of success, and new concepts emerging in ARDS therapy. Mayo Clin Proc. 2006;81(2): APC = activated protein C; ARDS = acute respiratory distress syndrome; BAL = bronchoalveolar lavage; FiO 2 = fraction of inspired oxygen; IL = interleukin; KGF = keratinocyte growth factor; NF-κB = nuclear factor κb; PAI-1 = plasminogen activator inhibitor 1; PaO 2 = arterial oxygen pressure; PGE 1 = prostaglandin E 1 ; TFPI = tissue factor pathway inhibitor; TNF-α = tumor necrosis factor α Acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and Petty in 1967 in a series of patients with dyspnea, hypoxia refractory to treatment, decreased lung compliance, and diffuse alveolar infiltrates apparent on chest x-ray films. 1 The current definition of ARDS was established by the American-European Consensus Conference Committee in 1994 to include acute onset of symptoms, bilateral patchy air space disease identified during chest x-ray examination, lack of evidence of left-sided heart failure or pulmonary capillary wedge pressure of less than 18 mm Hg, and differentiation of ARDS from acute lung injury by shunt severity. Acute lung injury is defined as the ratio of arterial oxygen pressure (PaO 2 ) to fraction of inspired oxygen (FiO 2 ) of 300 or less, and ARDS is defined as a PaO 2 /FiO 2 ratio of 200 or less. 2 The annual incidence of ARDS has been difficult to determine but is estimated at 150,000 cases per year or 75 per 100,000 population in the United States. The mortality of patients with ARDS is reported to be extremely high at 40% to 50%. 3 Strategies for treating ARDS have been extensively investigated. The only intervention that has shown a clear survival benefit is the use of low tidal volume mechanical ventilation of 6 ml/kg as opposed to traditional tidal volumes of 10 to 15 ml/kg. 4 The ARDS Network trial showed a 22% relative mortality reduction in patients treated with low tidal volume ventilation, possibly from decreased mechanical injury to lung endothelium and epithelium and a downregulation of proinflammatory cytokines. Further study of low vs high positive end-expiratory pressure in patients with ARDS showed no significant outcome differences. 5 Although progress has been made in ventilator strategies, no pharmacological intervention has proved effective. The ineffectiveness of drug therapy for ARDS is difficult to understand given advances in understanding the mechanisms of development and promising results seen from animal models. PATHOPHYSIOLOGY Knowledge of the pathophysiology of ARDS is necessary to understand drug treatments that have been investigated. ARDS arises as a complication of a direct or indirect lung insult. Some common ARDS precipitants include sepsis, nosocomial pneumonia, aspiration of gastric contents, pancreatitis, trauma, near drowning, inhalation injury, and drug overdose. 6 Within 72 hours of the precipitating event, a cascade of inflammation results in diffuse alveolar damage. ARDS is often divided into 2 main phases, starting with the initial inflammatory response, known as the exudative phase, followed closely by a repair process, known as the fibroproliferative phase. The third phase is termed the recovery phase and is characterized by improved oxygenation and lung compliance. 6 Some patients eventually have complete resolution of lung injury, whereas others are left with residual functional impairment, including muscle weakness, and decreased pulmonary function, including low carbon monoxide diffusion capacities 1 year after the initial event. 7 The exudative phase typically spans the first week after the onset of symptoms. It is characterized by increased permeability of both the capillary endothelium and the alveolar epithelium, resulting in an influx of plasma proteins into alveoli. Large numbers of neutrophils migrate into the area, and these neutrophils, in addition to activated alveolar macrophages, release oxidants; proteases; leukotrienes; proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin (IL) 1, and IL-8; and From the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex. Individual reprints of this article are not available. Address correspondance to Anthony DalNogare, MD, Department of Internal Medicine, Pulmonary and Critical Care Division, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX ( Anthony.DalNogare@UTSouthwestern.edu) Mayo Foundation for Medical Education and Research Mayo Clin Proc. February 2006;81(2):

2 anti-inflammatory cytokines, including IL-10 and IL-11. Activation of the extrinsic clotting pathway by tissue factor and inhibition of fibrinolysis by plasminogen activator inhibitor 1 (PAI-1) result in the formation of fibrin-rich hyaline membranes. Inactivation of surfactant also occurs, which contributes to alveolar collapse. Physiologically, the ARDS lung becomes heavy and noncompliant. Simultaneous with these alveolar changes, microthrombi composed of platelets and fibrin occlude small vessels, whereas release of vasoactive substances, including arachidonic acid metabolites, increases pulmonary vascular resistance, resulting in mild pulmonary hypertension. 1,6,8 The fibroproliferative phase typically occupies the second and third weeks and is characterized by type 1 pneumocyte necrosis, leading to filling of the alveolar lumen with leukocytes, red blood cells, and fibrin, whereas type 2 pneumocytes proliferate and differentiate into type 1 cells in an effort to restore the alveolar epithelial surface. Fibroblasts invade the interstitium and eventually the alveoli, depositing collagen and thickening alveolar walls. In fact, total lung collagen content often doubles within 2 weeks. The resultant fibrosis reduces compliance and increases the work of breathing, and alveolar obliteration combined with interstitial thickening leads to poor gas exchange. Simultaneously, intimal proliferation narrows vessels and sustains pulmonary hypertension. 1,6,8 Of note, the phases in ARDS are not temporally distinct. The fibroproliferative phase has been shown to begin much earlier than was previously thought. 8 In fact, studies have shown a marked increase in N-terminal procollagen III peptide, a marker for collagen turnover in bronchoalveolar lavage (BAL) fluid, within 24 hours of ARDS onset. This is particularly interesting because, although the inflammatory and fibroproliferative phases of ARDS overlap, they may be controlled by different mechanisms, which increase the possible targets and time frames for treatment options. Much still needs to be understood about the regulatory factors and pathways involved in ARDS. ANTI-INFLAMMATORY THERAPY Corticosteroids. Because ARDS is initiated by excessive inflammation, corticosteroids were the earliest treatment evaluated. Corticosteroids inhibit production of inflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-8. In addition, corticosteroids may have a role in decreasing collagen deposition by accelerating fibroblast procollagen messenger RNA degradation. 9 In the 1980s, several trials of early short-term, high-dose methylprednisolone treatment every 6 hours for 24 to 48 hours showed no decrease in mortality In the 1990s, a small multicenter study examined low-dose corticosteroids administered for more than 7 days with the hope of targeting the fibroproliferative phase by lessening collagen deposition. The trial consisted of 24 patients who had been receiving mechanical ventilation for more than 7 days and were randomized to receive daily methylprednisolone at 2 mg/kg for 32 days vs placebo. 12 There was a marked reduction in hospital mortality in the methylprednisolone-treated group (12%) vs the placebo group (62%) (P=.04). No increase in infectious complications occurred. Limitations of this study include the small number of patients, unequal groups with 16 patients in the treatment group and 8 patients in the placebo group, and a crossover of 4 placebo patients into the methylprednisolone group. Nonetheless, these positive results have prompted a large, ongoing ARDS Network trial called the Late Steroid Rescue Study. 12,13 Prostaglandin. The interest in prostaglandin E 1 (PGE 1 ) as a treatment option for ARDS is based on its function as an anti-inflammatory mediator and vasodilator. 14 In an early, single-center randomized controlled trial performed with trauma patients, nebulized PGE 1 showed improved survival of 71% at 30 days vs 35% survival in the placebo group. 15 However, in a subsequent randomized multicenter study of patients with ARDS from trauma or sepsis, improved mortality could not be shown, and PGE 1 administration was complicated by systemic hypotension. 16 The systemic effects of PGE 1 can be partly overcome by using liposomes to deliver the drug in a lung-targeted manner, but even with this advancement, there has been no survival benefit or reduction in ventilation time. 17,18 PHARMACOLOGICAL THERAPIES INVESTIGATED Many ARDS pharmacotherapies, including corticosteroids, nitric oxide, surfactant, ketoconazole, lysofylline, N- acetylcysteine, and fish oil, have initially shown efficacy in animal models but have not had clinical success. This review explores the pharmacological treatments studied clinically, proposed reasons for their lack of success, and new concepts emerging in ARDS therapy. VASODILATORS Inhaled Nitric Oxide. Nitric oxide is a natural free radical gas produced in the lungs by nitric oxide synthase from L-arginine, reduced nicotinamide adenine denucleotide phosphate, and oxygen. Nitric oxide relaxes pulmonary vascular smooth muscle and thus has important regulatory effects on regional lung ventilation and perfusion ratios. Inducible nitric oxide synthase is up-regulated by many cytokines and endotoxin. Using a murine endotoxin-induced lung injury model, Ullrich et al 19 showed that during inflammation nitric oxide synthase derived nitric oxide blocks normal hypoxic pulmonary vasoconstriction and contributes to the intrapulmonary shunt 206 Mayo Clin Proc. February 2006;81(2):

3 characteristic of ARDS. This study suggests that inhibition of nitric oxide synthase should maintain hypoxic vasoconstriction during ARDS and lessen shunting. Although endogenous nitric oxide, produced from nitric oxide synthase, impairs gas exchange during ARDS, exogenous inhaled nitric oxide relaxes vascular smooth muscle that supplies ventilated alveoli and thus may improve ventilation-to-perfusion relationships. 19 In 1993, Rossaint et al 20 published data showing that inhaled nitric oxide reduced pulmonary artery pressures and increased arterial oxygenation without producing systemic vasodilation. Despite its beneficial effect on PaO 2, several large multicenter trials have shown no survival benefit with inhaled nitric oxide Additionally, adverse effects of inhaled nitric oxide have been noted, including methemoglobinemia, production of toxic compounds such as nitrogen dioxide and peroxynitrate ion, increased pulmonary edema, and rebound pulmonary hypertension. Interestingly, recent trials using inhaled nitric oxide for preterm infants with respiratory failure have shown conflicting results. 26,27 One study showed that death or chronic lung disease occurred in 49% of infants treated with nitric oxide vs 65% in the placebo group (P=.03), whereas the other showed that treatment with inhaled nitric oxide resulted in no overall survival benefit. The differing results are thought to be due to differences in patient demographics, severity of illness, and study design. 28 Further trials are under way to resolve these discrepancies in infants, but the results in adults have been consistently negative. Prostacyclin. Prostacyclin is an endothelium-derived vascular smooth muscle relaxant that also inhibits platelet aggregation and neutrophil adhesion. Thus far, studies have shown fairly comparable results between inhaled nitric oxide and prostacyclin in terms of decreased pulmonary vascular resistance, decreased pulmonary artery pressures, and improved arterial oxygenation and shunt fraction. Prostacyclin may have some benefits over nitric oxide in that it is relatively simple to administer and has harmless metabolites, but it is more expensive and has also not shown any clear survival benefit in clinical trials. 29 DECREASED ALVEOLAR SURFACE TENSION The rationale for surfactant treatment of ARDS is based on several observations. 30 Normal surfactant, a mix of phospholipids and 4 proteins (A, B, C, D), lowers surface tension and thus prevents alveolar collapse. Surfactant proteins A and D are important for generating an innate immune response, and surfactant also has anti-inflammatory and antimicrobial properties. ARDS surfactant is abnormal because of decreased production by injured type 2 alveolar cells, increased removal, and altered composition with an increased proportion of relatively inactive forms. Surfactant obtained by BAL from ARDS patients is dysfunctional, with decreased surface tension lowering activity compared with that from healthy patients. Although exogenous surfactant replacement improves survival in premature infants with hyaline membrane disease, it has not been proved effective in treating ARDS. 31 Several randomized controlled studies have been performed using various preparations, doses, and methods of surfactant administration, and none have shown a mortality benefit. 30,32,33 However, one study showed a decrease in FiO 2 requirement. 32 A recent multicenter randomized controlled trial was conducted in 448 adult ARDS patients who received recombinant protein C based surfactant. Surfactant-treated patients had improved gas exchange and oxygenation, but no difference occurred in the number of ventilator-free days or 28-day mortality. 34 A recently published multicenter trial of infants, children, and adolescents with ARDS using calfactant, a natural surfactant with high surfactant protein B levels, showed a mortality benefit in treated patients. However, this study had only 153 patients, and infants made up 26% of the population. 35 Surfactant studies have been criticized for a variety of reasons, including use of protein-free surfactant preparations; use of aerosolized surfactant, which delivers less than 5% of the compound to distal alveoli; and short treatment periods. 33 Thus, although a clear mortality benefit has not been shown for surfactant administration in adults with ARDS, investigation of different surfactant preparations and dosing regimens is ongoing. PHOSPHATIDIC ACID INHIBITION Circulating free fatty acids levels are elevated in patients with ARDS. Inflammatory cytokines such as TNF-α and IL-1 activate phospholipase A 2 and acyltransferase enzymes, converting these fatty acids into proinflammatory mediators. Lisofylline is a xanthine derivative that inhibits lysophosphatidic acyltransferase and decreases release of cell membrane derived free fatty acids. 36 In addition to its effect on free fatty acids, lisofylline lowers TNF-α, IL-1, and IL-6 levels. 37 The ARDS Network conducted a multicenter randomized double-blind, placebo-controlled trial of lisofylline vs placebo administered to 235 patients with ARDS. The treatment group received lisofylline at 3 mg/kgup to 300 mg intravenously every 6 hours for 20 days. The study was stopped early for failure to show differences in prespecified outcomes, including resolution of organ failure, ventilator-free days, and infectionrelated deaths. Mortality in the lisofylline group at 28 days was 31.9% vs 24.7% in the placebo group. 37 At this point, lisofylline does not appear to have a role in treating ARDS. Mayo Clin Proc. February 2006;81(2):

4 THROMBOXANE SYNTHASE AND 5-LIPOXYGENASE INHIBITORS Pulmonary vascular smooth muscle cells, endothelial cells, platelets, and neutrophils release arachidonic metabolites, including thromboxanes and leukotrienes. Thromboxanes increase platelet aggregation, vascular tone, and lung permeability, whereas leukotrienes cause bronchoconstriction and act as a potent neutrophil chemokine. 38 Ketoconazole is a synthetic imidazole antifungal that inhibits thromboxane and leukotriene synthesis via inhibition of 5-lipoxygenase. It does not inhibit cyclooxygenase and thus does not affect prostacyclins or prostaglandins. 39,40 Three major clinical trials have administered ketoconazole prophylactically to prevent ARDS in high-risk, critically ill patients, with one of these reporting lower mortality with the use of ketoconazole The ARDS Network thus initiated a multicenter randomized, double-blind, placebo-controlled trial of 234 patients with ARDS who received placebo vs enteral ketoconazole, 400 mg/d, for treatment up to 21 days. The study was unable to show a statistically significant difference between the 2 groups in markers of gas exchange, ventilator-free days, or mortality. Interestingly, urinary thromboxane B 2 levels were not decreased in the ketoconazole group, suggesting that the ketoconazole dose used was insufficient to decrease thromboxane synthesis. 41 ANTIOXIDANTS Reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide, and hydrochlorous acid, are produced by neutrophils, alveolar macrophages, and pulmonary endothelial cells during ARDS. Indices of oxidative damage, including lipid peroxidation, protein degradation, and further neutrophil recruitment, are higher in patients who die of ARDS. Healthy lungs contain antioxidants, such as glutathione, superoxide dismutase, and catalase, which provide defense against these radical oxygen species and their harmful effects, and glutathione has been shown to be depleted in the lungs of patients with ARDS. 10 Thus, agents such as N-acetylcysteine and procysteine, which increase glutathione levels in the lungs, have been used to treat ARDS. The results of animal studies of N- acetylcysteine were favorable, but human trials were not as successful. 42 One randomized, double-blind, placebo-controlled trial of 66 patients with ARDS compared N- acetylcysteine treatment at 150 mg/kg hourly for 6 days vs placebo. No improvement occurred in oxygenation or survival in the N-acetylcysteine treated group. 43 Another study administered N-acetylcysteine, procysteine, and placebo to 3 groups in a randomized, double-blind, placebocontrolled trial of 46 patients with ARDS. The 2 treatment groups had increased glutathione stores and improved lung function, with the largest benefit being seen in the procysteine-treated group, but no significant difference in survival occurred. 44 Another study of 61 patients with acute lung injury randomized treatment with N-acetylcysteine, 40 mg/kg daily intravenously, vs placebo for 3 days. The N-acetylcysteine treated group had better oxygenation and less ventilatory support but did not have reduced mortality. 45 Currently, no clear evidence exists that N-acetylcysteine or procysteine improves ARDS mortality. IMMUNONUTRITION Supplying appropriate nutrition to intensive care unit patients has become an area of increasing interest, and manipulating diet composition to decrease endogenous inflammatory mediator release has been investigated as another method to treat ARDS. In animal models, fish oil or eicosapentaenoic acid enriched diets reduce lung inflammation. Fish oil and borage oil enriched enteral feeding was administered to 51 patients with ARDS. 46 Compared with standard nutrition controls, the patients consuming fish oil diets had fewer BAL neutrophils at days 4 and 7, improved oxygenation, and fewer ventilator days, but no effect on mortality was seen. A meta-analysis of 12 randomized controlled trials comparing standard enteral nutrition with antioxidant nutrition found decreased rates of infection but again no effect on mortality. 47 Other dietary components, including ascorbic acid, tocopherol, and flavonoids, which scavenge reactive oxygen species, are also currently being tried in patients with ARDS. 48 PROBLEMS WITH STUDIES OF ARDS TREATMENT Many different agents have been evaluated as treatment for patients with ARDS, and although some end points have improved, none have decreased mortality. Most agents have shown a clear improvement in survival in animals but have failed to show similar results in humans. There are several explanations for this. Patients with ARDS are a heterogeneous population with a variety of initiating events. In some, ARDS develops from direct lung injury, such as pneumonia, aspiration, and inhalation injury, whereas others have indirect lung injury from sepsis, trauma, pancreatitis, and transfusions. 7 Therapeutic outcomes may be different for these 2 classes of diseases. Animal models have typically been created with acid- or endotoxin-induced injury that causes ARDS, which may be a poor model of ARDS physiology. These models may not mimic the heterogeneity of humans and the variability of their immune and inflammatory responses during ARDS. Additionally, in animal models, most successful treatments are administered before ARDS onset, whereas clinically ARDS recognition and treatment are delayed. Thus, identi- 208 Mayo Clin Proc. February 2006;81(2):

5 fying ARDS risk factors and treating patients prophylactically, before the entire cascade of inflammation and fibrosis begins, may be a more fruitful approach. With more information regarding risk factors for ARDS, agents such as ketoconazole may prove to have a more consistent benefit as a prophylactic agent. Predictors of ARDS risk are currently being investigated. Thus far, indices of hypoxemia have not been shown to be a good predictor of clinical course. One demographic risk factor that has been identified is chronic alcoholism. Alcohol depletes lung glutathione stores, resulting in impaired antioxidant defense and predisposing lung cells to injury. 49 Further investigations into genetic features that may regulate ARDS susceptibility, such as TNF promoter polymorphisms, are also being pursued. 50 Another explanation for the failure of pharmacological ARDS treatment may be technical. For example, surfactant has shown a clear benefit in infants with respiratory distress syndrome and has shown improved oxygen indices in patients with ARDS but has not shown any mortality benefit in adults. It is possible that the correct formulation, method of delivery, or timing of surfactant administration has not yet been found. A similar explanation may exist for inhaled nitric oxide. Furthermore, ARDS has at least 2 early phases that are closely intertwined, the exudative phase and the fibroproliferative phase. It is likely that more than one phase of ARDS needs to be targeted to see a mortality benefit. In addition, long-term effects of ARDS have become an evolving area of interest, and no drug trials have focused on targeting the later stages. A great deal still needs to be learned about the signaling pathways, patterns of gene expression, and functional responses involved in these pathways to develop tailored ARDS therapy, but combination therapy may be necessary to see a clinically meaningful improvement. 48 Finally, most ARDS deaths are due to multiorgan failure. Less than 5% of patients actually die of refractory hypoxemia. 48 Since the primary end point of most studies is mortality, patients may be improving from a pulmonary standpoint but may not show mortality benefit because of extrapulmonary organ failure. Thus, ARDS treatment may need to focus more on preventing systemic inflammation and multiorgan failure than on recovery from lung injury itself. FUTURE PHARMACOLOGICAL TREATMENT STRATEGIES Although the results of clinical trials for pharmacological treatment of ARDS have been disappointing, several promising treatment strategies are still evolving, including agents to enhance edema clearance, stimulate repair of pathways, prevent fibrin formation, inhibit proinflammatory transcription factors, block new vasoconstrictors, and target inflammatory cytokines. INCREASED CLEARANCE OF ALVEOLAR EDEMA It is well known that increased alveolar permeability initiates pulmonary edema in ARDS, and understanding the molecular and cellular mechanisms involved in resolution of this edema has been an area of intensive research. Previously, sodium and fluid movement across the alveolar epithelium was thought to be due to passive diffusion secondary to osmotic and hydrostatic pressures. Although this is true, studies have established that active salt and water transport across alveolar epithelium also occurs, via Na + channels on the apical membrane of type 2 alveolar cells and Na + K + adenosine triphosphatase pumps on the basolateral surface. 51 These channels are thought to be positively regulated by catecholamines. Water channel proteins, called aquaporins, are also on the basolateral membranes of alveolar type 2 cells for fluid transport. As yet, no evidence exists that type 1 epithelial cells are involved in active Na + transport. Several strategies to target these channels for enhanced alveolar fluid clearance have been evaluated. 52 The β- adrenergic receptor agonists, including salmeterol, terbutaline, and isoproterenol, have been shown to activate Na + transport via the apical Na+ channels and basolateral Na + K + adenosine triphosphatase pumps, likely by cyclic adenosine monophosphate driven mechanisms In addition, agents such as dobutamine increase alveolar liquid clearance by approximately 50% in rats. The effect of dobutamine is thought to be mediated by β 2 -receptors because in that same study dopamine had no effect on alveolar fluid clearance. 56 However, in another rat study, intra-alveolar dopamine increased alveolar liquid clearance, implying a β 1 -mediated mechanism as well. 57 Inflammatory mediators, including macrophage migration inhibitory factor and TNF-α, increase aquaporin 1 expression in cultured lung endothelial cells in vitro and thus may increase alveolar fluid clearance as well. 58 Compounds that target active Na + and water channels on type 2 alveolar epithelial cells are currently being evaluated in phase 2 trials. ENHANCED REPAIR OF ALVEOLAR EPITHELIUM A characteristic of the fibroproliferative phase of ARDS is necrosis of type 1 alveolar cells and proliferation of type 2 cells. The increase in type 2 pneumocytes protects alveoli from further influx of protein-rich fluid and increases salt transporters and water channels available for fluid removal, and keratinocyte growth factor (KGF) is a potent stimulator of type 2 pneumocytes. One group of investigators administered KGF intrabronchially to rats with acid-induced Mayo Clin Proc. February 2006;81(2):

6 ARDS. They found that compared with placebo treatment, KGF-treated rats had an increase in septal cuboidal cells, which expressed surfactant protein C, a marker of type 2 cells. However, they were unable to show a mortality benefit. 59 Another study of rats with hyperoxia-induced lung injury showed a 5-fold increase in type 2 cells undergoing mitosis and found a reduction in mortality in the rats treated with 1 or 5 mg/kg of recombinant human KGF relative to controls (P<.001). 60 Other growth factors, including transforming growth factor β, are also being evaluated. INHIBITION OF FIBRIN FORMATION Alveolar, interstitial, and intravascular fibrin deposition is a well-recognized histological finding in ARDS. Fibrin formation is initiated by tissue factor, which activates factor VII and the extrinsic pathway. Fibrin deposition enhances the inflammatory response via IL-1 and IL-6, increases vascular permeability, and activates neutrophils. Working against this process, regulatory mechanisms limiting coagulation involve antithrombin III, protein C, protein S, tissue factor pathway inhibitor, and PAI In the first 3 days of ARDS, a profound procoagulant effect occurs, leading to exuberant fibrin deposition. During the following 10 to 12 days, this response gradually declines, but fibrinolysis is minimal due to overexpression of PAI-1. It is this combination of up-regulation of coagulation initially followed by down-regulation of fibrinolysis that results in persistent fibrin deposition. 62 Two anticoagulants, activated protein C (APC) and tissue factor pathway inhibitor (TFPI), have thus far shown promise for treatment of sepsis. Activated protein C inhibits factor Va and VIIIa and exerts anti-inflammatory effects by decreasing production of TNF-α, IL-1, and IL-6 and neutralizing PAI-1. In a large multicenter randomized controlled trial that included 1690 patients with sepsis, the treatment group was given intravenous APC for 96 hours. Mortality rate was reduced from 30.8% in the placebo group to 24.7% in the APC-treated group (P=.005). However, the incidence of bleeding increased from 2.0% to 3.5% in the treated patients. 63 A subgroup analysis of patients with ARDS was not provided in that study, but given the overlapping mechanisms of sepsis and ARDS, APC may show mortality benefit in patients with sepsis-induced ARDS as well. Tissue factor pathway inhibitor is a molecule that forms a complex with tissue factor, factor Xa, and factor VIIa to block coagulation through the extrinsic pathway. In a small phase 2 trial of patients with sepsis, TFPI was tested and showed a 20% relative reduction in 28-day mortality. 64 Results of ARDS subgroup analysis showed a survival advantage in the treated group. Unfortunately, the phase 3 trial of TFPI in patients with sepsis failed to show mortality benefit and showed an increased risk of bleeding. 65 Activated protein C has already shown its benefit in treating patients with sepsis, but it is unclear whether it will have any benefit in non sepsis-induced patients with ARDS, particularly trauma patients. Both APC and TFPI need to be further evaluated in studies with a primary focus on patients with ARDS of all causes to understand what portion of procoagulant response is harmful and what is helpful in various causes of lung injury as well as the optimal time to administer these compounds. INHIBITION OF NUCLEAR FACTOR κb Nuclear factor κb (NF-κB) is a transcription factor that up-regulates many important inflammatory mediators, including TNF-α, IL-1, IL-2, IL-6, and IL In most cells, cytoplasmic NF-κB is dormant in the cytoplasm because it is bound to inhibitors. On appropriate stimulation of the cell, these inhibitors are phosphorylated and undergo proteolytic degradation, releasing active NF-κB, which can move to the nucleus and induce expression of many genes. Nuclear factor κb up-regulates expression of cytokineinduced neutrophil chemoattractant, which has been shown to be an important factor in neutrophil recruitment and inflammation in rats. Activation of NF-κB in vivo depends on generation of reactive oxygen species. Thus, N-acetylcysteine, an antioxidant, may inhibit NF-κB activation. In a rat study, N-acetylcysteine was injected 1 hour before endotoxin administration, and the N-acetylcysteine treated animals showed decreased cytokine-induced neutrophil chemoattractant messenger RNA expression and less neutrophilic alveolitis. Treatment in this study was initiated before development of lung injury, but NF-κB as a target pathway for ARDS treatment represents an attractive area that merits further study. ENDOTHELIN RECEPTOR ANTAGONIST Increased plasma levels of endothelin 1, a primarily endothelium-derived vasoconstrictor, have been found in patients with ARDS. As the patients recover, endothelin 1 levels decrease, which suggests that endothelin 1 may have a role in the pathogenesis of ARDS. 67,68 An endothelin receptor antagonist, tezosentan, was evaluated in sheep with smoke inhalation and burn injury. Treated vs control animals showed no difference in PaO 2 /FiO 2 ratio, but pulmonary vascular resistance and bronchiolar obstruction decreased, whereas lung lymph flow increased in the treated group. No clear protection against acute lung injury could be seen in this model. 69 However, another group of investigators designed an experiment to evaluate the role of tezosentan in treated sheep with endotoxin-induced lung injury. Results showed that treated animals had decreased pulmonary hypertension, cardiac dysfunction, pulmonary edema, and hypoxemia. 70 These positive results support the 210 Mayo Clin Proc. February 2006;81(2):

7 need for further investigation of endothelin receptor antagonists in treating ARDS. ANTICYTOKINE THERAPY Studies have shown that BAL fluid levels of inflammatory cytokines, such as TNF-α, IL-1, IL-2, IL-4, IL-6, and IL-8, may predict outcome in patients with ARDS. This finding suggests a causal relationship among inflammatory cytokines, lung inflammation, and progression of fibroproliferation. 71 Interleukin 8 is produced by alveolar macrophages, type 2 pneumocytes, and pulmonary fibroblasts and is a major chemotactic factor for neutrophil recruitment. Interleukin 8 also mediates neutrophil migration across vascular endothelium. In a study of acidinduced lung injury in rabbits, treatment with anti IL-8 monoclonal antibody was given 5 minutes before and 1 hour after acid instillation, and neutralization of IL-8 was confirmed in the lung. At 24-hour follow-up, anti IL-8 given 1 hour after acid instillation led to a more than 50% decrease in neutrophil influx and to a decrease in severity of acute lung injury as measured by lung edema, alveolararterial gradient, arterial carbon dioxide, and peak airway pressures. These experimental results imply that anti IL-8 antibodies may have a role in preventing ARDS from gastric aspiration in particular. However, there are concerns that anti IL-8 treatment might increase the risk of infection and blunt protective aspects of the host inflammatory response. 72 Evaluation of other anticytokine antibodies, including anti TNF-α, anti IL-1, and anti IL-10 antibodies, are currently under way as well. 73 CONCLUSION Despite the discouraging results of pharmacotherapy for ARDS thus far, lung protective mechanical ventilation strategies and effective treatment for sepsis with APC have helped improve care for these patients. Promising but untested strategies for treating ARDS include earlier administration of drugs to patients at risk of ARDS and use of combination drug regimens to target multiple developmental mechanisms. As our understanding of ARDS continues to evolve, promising therapeutic ideas are being explored, such as stimulation of epithelial channel proteins to control pulmonary edema, enhanced type 2 pneumocyte proliferation to repair damaged alveoli, and use of anticytokine antibodies to directly target inflammatory mediators. Further translation of information about signaling pathways, regulation of pulmonary inflammation, and genetic and environmental factors involved will be needed to develop systemic approaches for effective pharmacotherapy for ARDS. REFERENCES 1. Weinacker AB, Vaszar LT. Acute respiratory distress syndrome: physiology and new management strategies. Annu Rev Med. 2001;52: Bernard GR, Artigas A, Brigham KL, et al. 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