Potential Mechanisms by which Statins Modulate the Development of Acute Lung Injury

(1)

Development of Acute Lung Injury

T. Craig, C. O’Kane, and D. McAuley

Introduction

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by acute hypoxemic respiratory failure and bilateral pulmonary infil- trates that are not attributable to left atrial hypertension [1]. ALI/ARDS is a hetero- geneous disease with a complex pathophysiology that may occur in response to a direct pulmonary or indirect systemic injury [1]. ALI and ARDS are different spec- trums of the same condition. ALI is characterized by a PaO₂/FiO₂ratio of less than 300 mmHg (40 kPa). ARDS, the more severe end of the spectrum on the basis of oxygenation criteria, is defined by a PaO₂/FiO₂ ratio of less than 200 mmHg (26 kPa). A recent prospective cohort study estimated the incidence of ALI to be 79/

100,000 person years [2]. Mortality remains high although more recent trials have reported a lower mortality [3, 4].

Limiting tidal volume and, thereby, lung over-distension is the only maneuver that has been proven by clinical trials to improve the mortality of patients with ARDS [3]. Despite advances in mechanical ventilation strategies, it is becoming increasingly apparent that even the best ventilation strategy further damages the injured lung [5]. There is, therefore, a major need to develop a pharmacological agent to improve clinical outcome in ALI/ARDS.

Many treatment options including anti-inflammatory agents, antioxidants, pulmonary vasodilators, and surfactant replacement have been studied; however, despite extensive and ongoing research, no therapeutic option has been convincingly shown to decrease mortality in ALI/ARDS. Although, a small phase II clinical study has suggested that beta-agonists may have a potentially beneficial role [6], larger clinical trials are required to confirm this finding.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, were introduced into clinical practice in the 1980s. They were introduced as cholesterol lowering agents and considerable research has been focused on them.

Secondary prevention trials have provided insights into future potential applications of statin therapy. For example, the Long-term Intervention with Pravastatin in Ische- mic Disease (LIPID) [7] study suggested that the degree of cardiovascular benefit was in excess of the cholesterol lowering properties. There are now a large number of publications describing the pleiotropic effects of statins and as a result they may have other applications in clinical practice. This chapter will focus on interesting recent in vitro and in vivo animal and human studies that suggest that statins may modulate mechanisms important in ALI/ARDS.

(2)

Pathogenic Mechanisms of ALI/ARDS

The alveolar capillary unit is the site for gas exchange in the lung. This interface consists of two closely related barriers, the vascular endothelium and the alveolar epithelium. The alveolar epithelium consists of two cell types, the more common type I cell (90 %) important in gas exchange and the type II cell (10 %) involved in alveolar fluid clearance, surfactant production, and regeneration of type I cells following injury.

The pathogenesis of ALI/ARDS remains poorly understood. The majority of evidence suggests that neutrophil-mediated injury is central to the development of ALI/

ARDS [1]. Furthermore, the persistence of neutrophils in the bronchoalveolar lavage (BAL) fluid of patients with ALI/ARDS is associated with a higher mortality at day 7 [8]. Alveolar macrophages play a pathogenic role in conjunction with the influx of neutrophils [9]. These inflammatory cells release inflammatory cytokines, proteases, and, in particular, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) [1].

Inflammatory cytokines play an important role in the pathophysiology of ALI/

ARDS. Tumor necrosis factor (TNF)-[ , interleukin (IL)-1 q , IL-6, and IL-8 are found in BAL fluid and plasma of patients with ALI/ARDS. At the onset of ARDS, non-survivors have significantly higher BAL fluid concentrations of TNF-[ , IL-1 q , IL-6, and IL-8 (CXCL8); over time, pro-inflammatory cytokine levels remain persistently elevated in non-survivors [10]. Indices of endothelial permeability correlate with plasma and BAL fluid cytokines. However, no single cytokine predicts either the onset or the outcome of ARDS.

MMPs are a group of diverse zinc containing, proteases enzymes capable of degrading the extracellular matrix. They are produced by cells important in the pathogenesis of ALI/ARDS, including epithelial and endothelial cells, alveolar macrophages, neutrophils, and fibroblasts [11]. MMPs are regulated in part by tissue inhibitors of matrix metalloproteases (TIMPs). MMPs are classified according to their substrate specificity. The gelatinases (MMP-2 and MMP-9) are capable of degrading type IV collagen, the major extracellular matrix component of the basement membrane, which is characteristically disrupted in ARDS, appear to play a role in ALI/ARDS [12, 13]. More recently MMP-1, -2, and -8 have been identified in BAL fluid from patients with ALI/ARDS. MMP-1 and -3 are associated with disease sever- ity, including mortality [14].

This uncontrolled local inflammatory response causes alveolar epithelial and capillary endothelial barrier damage [15, 16] central to the development of lung injury.

The small GTPases, Rho and Rac, are involved in signal transduction linking extracellular stimuli to epithelial and endothelial barrier function [17]. Consequently, there is impaired gas exchange with resultant hypoxemia, reduced lung compliance, and the need for mechanical ventilation.

Classically, the fibro-proliferative phase follows, characterized by organization of the alveolar exudate and by fibrosis. There is type II cell proliferation. Lymphocytes and fibroblasts are the predominant cell types with evidence of matrix reorganiza- tion. However, it is now considered that these subdivisions of ALI/ARDS may not be clearly demarcated and there may be a degree of overlap in these pathological divi- sions.

(3)

Mechanism of Action of Statins

HMG-CoA reductase catalyzes the rate limiting step in the production of cholesterol.

Although the chemical composition of the statin may vary, they all inhibit the reductase site in the same manner; they inhibit the conversion of HMG-CoA to mevalonate. As a consequence of this action, the intermediates of the mevalonate pathway are also reduced (Fig. 1).

In addition to cholesterol production, the mevalonate pathway leads to the formation of isoprenoids such as geranylgeranylpyrophosphate (GGPP). Isoprenoids regulate prenylation, the addition of hydrophobic molecules to a protein. Protein prenylation involves the transfer of either a farnesyl or a geranylgeranyl moity to C- terminal cysteine(s) of the target protein. Lipid modification of proteins is necessary for interaction with cellular membranes. The isoprenoid intermediates are important in several signaling pathways, and regulate function of G proteins and the small GTP binding proteins, Ras, Rho, and Rac. The small GTP binding proteins control multiple cellular activities, including cell proliferation, generation of ROS and acti-

Fig. 1. The mevalonate pathway

(4)

vation of pro-inflammatory cytokines, all of which are important in the pathogenesis of ALI [1]. Inhibition of isoprenoid formation by statins, therefore, may have significant anti-inflammatory effects.

Most of the anti-inflammatory effects of statins are mediated by inhibition of the mevalonate pathway, as shown by the reversal of anti-inflammatory properties with the addition of mevalonate, GGPP, and farnesylpyrophosphate (FPP).

However, statins have additional properties independent of their HMG-CoA reductase inhibition. Lymphocyte function associated antigen-1 (LFA-1) or integrin [ 1q2(also known as CD11a or CD18) is a member of the integrin family and is found exclusively on leukocytes in an inactivated state. It plays a role in leukocyte extravasation and in T cell activation by antigen presenting cells. The main ligand of this adhesion molecule is the intracellular adhesion molecule 1 (ICAM- 1). Following binding of ICAM-1, LFA-1 provides a potent co-stimulatory stimulus for T cell receptor (TCR) activated T cells. Simvastatin inhibits the binding of LFA-1 to ICAM-1 [18]; as a result there is reduced lymphocyte adhesion to ICAM- 1 and reduced T cell costimulation. This action is only partially reversed by the addition of mevalonate, indicating that HMG-CoA reductase inhibition-independent mechanisms are involved. Interestingly, pravastatin did not affect the LFA-1- ICAM-1 interaction, indicating specificity among the statins rather than a class effect.

Molecular Mechanisms for the Anti-inflammatory Effects of Statins

Statins may modify the critical pro-inflammatory intracellular signaling pathways described below.

Transcription Factors: Nuclear Factor-kappa B and Activator Protein

Several pro-inflammatory stimuli converge on a few key transcriptional pathways.

Nuclear factor-kappa B (NF-κB) is one of the major transcription factors. It is found in the cytoplasm bound to its inhibitor, IκB. In response to inflammatory stimuli, the inhibitor is degraded with the active portion, leaving NF-κB free to translocate to the nucleus, where it binds to the promoter sequences of pro-inflammatory genes, inducing gene expression.

Activator protein-1 (AP-1) is another key transcription factor family regulating the induction of a series of pro-inflammatory genes. Like NF-κB the family consists of a series of subunits, such as Jun and Fos. Upregulation in AP-1 occurs in response to a series of stimuli including IL-1, which is a key mediator in the pathogenesis of lung injury. In turn AP-1 regulates the induction of many cytokines, including CXCL8, and some MMPs, which are also described in the pathophysiology of ARDS.

Simvastatin, lovastatin, and atorvastatin inhibit the binding of nuclear proteins to NF-κB and AP-1. They also upregulate the cytoplasmic inhibitor of NF-κB (IκB- [ ) in endothelial cells, preventing nuclear translocation and, therefore, induction of NF-κB-dependent genes. Statins also reduce the expression of c-Jun, a component of AP-1 [19].

(5)

Kruppel-like Factor 2

KLF2 is a member of the Kruppel-like family of transcription factors. These factors are important in the control of endothelial gene expression and in the regulation of multiple endothelial functions. Statins induce KLF2 expression via the Rho pathway [20]. Statins can induce factors including thrombomodulin and endothelial nitric oxide synthase (NOS).

Peroxisome Proliferator Activated Receptor-alpha

The activation of peroxisme proliferator activated receptor-(PPAR)-[ leads to the inhibition of inflammatory pathways. PPARs act by negatively interfering with NF- κB and AP-1 signaling pathways. Statins activate PPARs [21]. The addition of mevalonate reverses the PPAR-[ activation by statins indicating that it is the downstream products of the mevalonate pathway that inhibit PPAR-[ activity.

Mitogen-Activated Protein Kinases

The mitogen-activated protein kinases (MAPKs) are a group of intracellular signaling intermediates, activated by inflammatory cytokines and growth factors, which regulate gene expression, differentiation, and apoptosis. Key inflammatory cytokines, such as CXCL8, and most MMPs are regulated by MAPKs. Statins can directly inhibit the MAPK pathways, resulting in reduced cytokine/MMP gene expression.

For example, simvastatin inhibits granulocyte-macrophage colony stimulating factor (GM-CSF) induced by the Ras and Rho-p38 MAP kinase signaling cascade. This in turn results in inhibition of macrophage proliferation [22].

Statins and Leukocyte Activity

Neutrophil Function

Statins reduce neutrophil numbers in animal models of ALI/ARDS. In an endotoxe- mic model of ALI/ARDS, mice were pre-treated with 5 mg/kg or 20 mg/kg simvastatin or placebo injected intraperitoneally. This was administered 24 hours before and again concomitantly with intratracheal lipopolysaccharide (LPS, 2 µg/g body weight). Compared to placebo, mice treated with 20 mg/kg simvastatin had lower levels of BAL neutrophils and myeloperoxidase (MPO) activity (a marker of neutrophil activity) with an associated reduction in endothelial permeability as reflected by the 50 % reduction in BAL albumin. A reduction in lung injury was confirmed histologically [23].

In an ischemia-reperfusion model, rats were pretreated with simvastatin 10 mg/

kg daily or distilled water via an orogastric tube for 3 days. The intestinal ischemia- reperfusion injury was performed by occlusion of the superior mesenteric artery for 60 minutes followed by 90 minutes of reperfusion. Rats pretreated with simvastatin had improved oxygenation compared to the control group. There was also evidence of reduced lung injury indicated by a reduction in neutrophils and end products of free radical mediated injury and an improvement in endothelial permeability with a lower wet to dry ratio in the statin subgroup [24].

In a lung ischemia/reperfusion model (90 minute ischemic period and 4 hours of reperfusion) rats were pretreated with simvastatin 0.5 mg/kg orally. After 5 days of

(6)

simvastatin there was an 85 % reduction in vascular permeability. There was a significant reduction in MPO content and presence of leukocytes in the alveolar space in the statin treated group [25].

Statins can also inhibit leukocyte migration in response to chemotactic agents and also across the vascular endothelium. Cerivastatin has been demonstrated to reduce leukocyte chemotaxis to CXCL8. Migration was restored with the addition of mevalonic acid. Cerivastatin reduced transendothelial migration of neutrophils.

With elevated concentrations of cerivastatin, the rate of apoptosis in neutrophils and monocytes was also increased [26].

Monocyte Function

Statins regulate monocyte function. Pre-treatment of monocytes with lovastatin (20 – 40 mg) reduced the expression of CD11b and inhibited CD11b-dependent monocyte adhesion to the endothelium. Cd11b/CD18 is a q2integrin important in cell adhesion and signal transduction, and is found on the surface of monocytes.

The interaction of this integrin with ICAM-1 is important in the adhesion and migration of activated monocytes across the endothelium. Co-incubation with mevalonate but not low-density lipoprotein (LDL) reversed the effects of lovastatin.

This suggests that early precursors and not cholesterol mediate this effect [27].

Lymphocyte Function

In the later stage of ARDS, the number of neutrophils declines and there is an increase in numbers of lymphocytes and macrophages in BAL fluid. As discussed earlier, simvastatin, but not pravastatin, inhibits lymphocyte adhesion to ICAM-1 resulting in decreased T cell activation [18]

Statins: Effects on C-reactive Protein and Inflammatory Cytokines

Concentrations of C-reactive protein (CRP), a marker of inflammation, are decreased 15 – 30 % by pravastatin in patients with cardiovascular disease [28]. The level of CRP reduction does not correlate with the lipid lowering properties. This again supports the hypothesis that anti-inflammatory effects exist that are independent of cholesterol reduction.

In a murine model of systemic inflammation, lovastatin and simvastatin were administered 0.5 hours, 8 and 20 hours before the introduction of LPS. Both inhibited IL-6 and CCL2 secretion. The effect of blocking the activity of the enzyme that catalyzes the first step of the cholesterol pathway, after it branches to various nonsterol products, was also investigated (Fig. 1). Administration of a squalene synthe- tase inhibitor, squalestatin did not inhibit inflammatory cytokine secretion [29].

There is also in vitro and in vivo work indicating that statins can reduce mono- cyte derived IL-6, CXCL8, and CCL2 [30]. Patients with hypercholesterolemia were pre-treated with simvastatin 20 – 40 mg for 6 weeks. Following treatment there was a significant reduction in plasma CCL2, IL-6, and CXCL8. There was a similar reduction in the expression of IL-6, CXCL8, and CCL2 mRNA in peripheral blood mono- nuclear cells. Similar results were obtained in vitro by using cultured human umbili- cal vein endothelial cells and peripheral blood mononuclear cells from healthy nor- molipemic donors. Exposure to simvastatin, atorvastatin, or cerivastatin caused

(7)

downregulation of the expression of cytokine mRNA in a time- and dose-dependent manner.

The effect of pre-treatment with simvastatin prior to exposure to intravenous LPS was investigated in a double-blind, placebo controlled trial in healthy individuals.

Compared to placebo, after 4 days treatment with 80 mg simvastatin, the inflammatory response was blunted. CRP and CCL2 were significantly suppressed and the concentration of monocyte tissue factor was also inhibited in the statin group [31].

Published data show that a single dose of 80 mg simvastatin can reduce CRP levels in patients with unstable angina within 48 hours [32].

Statins and MMP Activity

As discussed above, MMP-9 has been implicated in the development of ALI/ARDS.

Macrophages are a major source of MMP-9. In vitro incubation of mice and human macrophages with statins is associated with reduced quantities of MMP-9 secretion [33, 34]. The effect is again reversible with the addition of mevalonate. In addition, cerivastatin inhibits macrophage MMP -1, and -3 [34] and neutrophil MMP-9 [33].

In patients with hypercholesterolemia and coronary artery disease randomized to receive 20 mg simvastatin or 200 mg fenofibrate for 8 weeks, both lipid-lowering agents resulted in a reduction in plasma TNF-[ . However, only the simvastatin group had a significant reduction in MMP-1, and -9 compared to the fenofibrate treated group [35]. Data suggest that statins may more effectively modulate the key inflammatory pathways driving ALI than fibrates, and further support the hypothesis that this effect is independent of lipid lowering.

Statins and Oxidative Stress

Increased oxidative stress is important in the development of ALI. ROS are detect- able in BAL fluid of patients with ALI. Through the inhibition of Rac isoprenylation, statins lead to a reduction in NADPH oxidase with a resultant reduction in ROS which may be beneficial in ALI [36].

Statins and the Endothelium

Endothelial dysfunction is central to the development of ALI [1]. The vascular endothelium has several important roles including regulation of vascular tone, permeability, blood flow, coagulation and inflammation. The effect of statins on the endothelium has been studied extensively. Statins improve endothelial function by increasing the bioavailability of NO with resultant increased vasodilatation [37].

This effect is mediated by various mechanisms including upregulation of eNOS expression.

Actin-myosin cytoskeletal organization determines endothelial permeability with Rho mediating increased permeability and Rac decreasing permeability in response to injury with thrombin [38]. Simvastatin attenuates the endothelial barrier dysfunction induced by thrombin. As expected by its mode of action (Fig. 1), simvastatin inhibited Rho but paradoxically Rac was activated. One potential explanation for this paradoxical observation is that the inhibition of prenylation preferentially

(8)

inhibits Rho and, via a normally tonic inhibitory effect on Rac, effectively increases Rac activation. Alternatively, specific inhibitors of Rac may be induced by simvastatin independent of the prenylation pathway. In addition, in a murine inflammatory model of ALI, simvastatin reduced BAL albumin by 50 % indicating an improvement in alveolar epithelial-capillary endothelial barrier permeability [23].

Von Willebrand factor (vWF), a marker of endothelial injury/activation is elevated in pulmonary edema fluid and plasma samples in individuals with ALI/ARDS.

Statins reduce plasma vWF levels over a sustained time period. In hyperlipidemic patients treatment with simvastatin resulted in a significant reduction in vWF after three months, which was sustained during a two-year follow up period [39].

Statins also affect the endothelium by their action on coagulation. Abnormalities of the clotting system occur in ALI [1]. Higher baseline levels of plasminogen activator inhibitor 1 (PAI-1) in ALI/ARDS are associated with a longer duration of ventilation and higher mortality [40]. Statins inhibit the expression of PAI-1 from human smooth muscle cells and endothelial cells in vivo. This effect is reversed by the addi- tion of mevalonate and GGPP but not FPP, suggesting that GGPP is required in the expression of PAI-1 [41].

Statins and the Alveolar Epithelium

In ALI/ARDS, an intact functioning alveolar epithelium is associated with improved outcomes, with regards to survival and duration on a ventilator [42]. Although there are few published data on the effect of statins on alveolar epithelial cell function, preliminary work published in abstract form has shown that statin treatment inhibits alveolar epithelial cell CXCL8 production [43]. Intact epithelial function requires tight junctions, and an intact basement membrane. Both tight junctions and basement membrane are degraded by MMPs (in particular MMP-2/-3/-7/-9) and given that statins reduce expression of these MMPs in vivo and in vitro, it is possible that statin treatment will improve epithelial barrier function.

Statins in Sepsis: Implications for ALI/ARDS

ALI is the most lethal complication of sepsis and has the highest mortality. There is now emerging evidence that statins may have a beneficial effect on clinical outcomes in sepsis.

In a murine model of sepsis, pre-treatment with simvastatin markedly increased survival time. Mice treated with simvastatin at 0.2 µg/g body weight had a median survival of 108 hours as opposed to 28 hours in the placebo group following cecal ligation and perforation. This appeared to be the result of preservation of cardiac function [44].

In addition, there have been several human observational studies, which have suggested a benefit with statins in septic patients [45 – 48]. The largest trial analyz- ing data from over 69,000 patients found a 19 % risk reduction of developing sepsis if pre-treated with a statin. This also applied to high risk groups defined by the presence of diabetes, renal impairment, and a history of recurrent infections. Interest- ingly, no benefit was noted with non-statin lipid-lowering agents [48].

Furthermore, statins decreased the risk of progression to severe sepsis [45] and reduced mortality attributable to sepsis [46]. Importantly, in one study, the reduc-

(9)

tion in both all-cause hospital mortality and death attributable to bacteremia was more marked in the patients who continued to receive statin therapy after the diag- nosis of bacteremia [47].

These studies support the concept that statins may have a potential role in the treatment for ALI/ARDS.

Statin Safety Profile

Most statins are metabolized by hepatic cytochromes. Pravastatin is metabolized by sulfation and not via the cytochrome pathway. Drugs that interfere with hepatic cytochromes, therefore, need to be used with caution in conjunction with statins.

Statins should be used with caution in those with liver disease. Treatment should be withheld or discontinued if serum transaminase concentrations persist three times above the upper level of normal.

Myopathy is the other important adverse effect associated with statin use. Treat- ment with statins should be withheld or discontinued if the creatine kinase (CK) is elevated five times above the upper level of normal [49].

The large quantities of data on the use of statins in cardiovascular disease can provide further insights into statin safety. One study randomized 2265 patients following a coronary event to receive simvastatin 80 mg or placebo. Even with high dose (80 mg) simvastatin, myopathy (CK 810 times the upper limit of normal associated with muscle symptoms) occurred in only 0.4 % and rhabdomyolysis (CK 8 10,000 units/l with or without muscle symptoms) in 0.13 % of patients [50]. Of note, treatment in this study lasted up to 24 months with follow-up only at months 1, 4, and 8, and every 4 months, thereafter, until trial completion.

There are concerns that critically ill patient may be at higher risk of adverse effects related to statins. However, the finding of greater reduction in all-cause hospital mortality in patients with sepsis who continued to receive statin therapy [47], and the fact that the duration of treatment in the critically ill patient with ARDS will be much shorter and that patients will be intensively monitored provides some reas- surance that adverse effects from statins may not be a greater problem in an intensive care patient population. However, ongoing pharmacovigilance is clearly required.

Which Statin?

Pleiotropic actions have been demonstrated for most statins but to date there have been no studies directly comparing these effects. Although the mode of action among the statins is similar, there do appear to be differences among their non-lipid lowering effects. For example, pravastatin does not inhibit LFA binding [18].

In the four observational sepsis studies [45 – 48], which statin was used was not consistently reported. However, in the reports which presented this information, although a range of statins was used, simvastatin was the most common.

Furthermore, in a double-blind, placebo-controlled study, simvastatin was effective in inhibiting the systemic inflammatory and procoagulant responses important in the development of lung injury [31]. No other clinical studies have been published.

Therefore, although there is limited evidence as to the most appropriate statin for use in ALI, the currently available data support the use of simvastatin.

(10)

Statin Dosage

Although there are large amounts of data suggesting statins may be beneficial in models of ALI, only a single animal study has compared two doses of simvastatin (5 or 20 mg/kg). Only the higher dose was effective in attenuating lung injury [23]. On a dose per unit body mass basis these doses are significantly higher than those used in humans.

The data from Steiner et al. involving healthy human volunteers exposed to LPS suggested an improvement in inflammatory indices after four days treatment with simvastatin 80 mg [31]. No other clinical studies demonstrating that a lower dose is effective have been published. The dosages of statins used in the observational sepsis studies were variable and although lower doses were more common, higher doses were also used [45 – 48].

Therefore, although clearly further work is necessary to determine the appropriate therapeutic dose which may be beneficial in the setting of ALI, on the basis of current available data, higher doses seem appropriate.

Duration of Treatment

Further research is required to determine the appropriate timing and duration of statin therapy, which may be effective in ALI/ARDS. Assuming that statins modulate mechanisms that are more important in the development and early phase of ALI/

ARDS these agents are more likely to be effective if they are commenced early after the onset of ALI/ARDS or as a prophylactic therapy in those at risk. Pleiotropic effects are seen early in the course of treatment with statins. In fact, in one study a reduction in CRP was seen by 48 hours after a single dose of simvastatin 80 mg [32].

The median duration of ventilation in ALI/ARDS is 6 (2 – 12) days [2] which has implications for the proposed duration of therapy. It is likely that a treatment duration of up to 14 days will be required.

Potential Limitations to Therapy

There are significant changes in lipid metabolism in patients with sepsis. It appears that while triglyceride levels are elevated, there is a reduction in total cholesterol.

The mechanism for this remains unclear but it may have implications for statin use in sepsis-induced ALI/ARDS. It is possible that HMG-CoA reductase is already max- imally downregulated and that any benefit of additional inhibition by statins will be limited. However, the beneficial effects in sepsis [45 – 48], in addition to the actions independent of HMGCoA reductase inhibition [18], would suggest that they will provide additional potential benefit.

Conclusion

There is considerable evidence from in vitro, in vivo animal, and observational human studies to suggest that statins may have a role in the management of ALI/

ARDS. However, at present there are insufficient clinical data to recommend their use in ALI/ARDS.

(11)

A phase II clinical trial is currently underway examining the effect of treatment with simvastatin 80 mg in patients with ALI/ARDS (the Hydroxy-methyl glutaryl CoA reductase inhibition in ALI to Reduce Pulmonary edema (HARP) study- ISRCTN 70127774). A further study investigating whether simvastatin can prevent the development of ALI/ARDS is planned in at risk patients. Results from these clinical trials will help define the role of statins in the prevention and treatment of ALI/

ARDS.

References

1. Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:

1334 – 1349

2. Rubenfeld GD (2005) Incidence and outcomes in acute lung injury. N Engl J Med 363:

1685 – 1693

3. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301 – 1308

4. The National Heart Lung and Blood Institute Acute Respiratory Distress Network (2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564 – 2575

5. Hager DN, Krishnan JA, Hayden JL, Brower RG (2005) Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 172:1241 – 1245

6. Perkins G, McAuley D, Thickett D, Gao F (2006) The b-Agonist Lung Injury Trial (BALTI) A randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 173:281 – 287 7. The Long term Intervention with Pravastatin in Ischemic Disease (LIPID) study group (1998)

Prevention of cardiovascular events and death with pravastatin in patients with coronary artery disease and a broad range of cholesterol levels. N Engl J Med 339:1349 – 1357 8. Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD (1994) Evolution

of bronchoalveolar cell populations in the adult respiratory distress syndrome Am J Respir Crit Care Med 150:113 – 122

9. Frank J, Wray C, McAuley D, Schwendener R, Matthay M (2006) Alveolar macrophages con- tribute to epithelial barrier dysfunction in ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 291:L1191 – 1198

10. Meduri GU, Headley S, Kohler G, et al (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and effi- cient predictors of outcome over time. Chest 107:1062 – 1073

11. O’Kane CM, Frank JA, McAuley DF (2004) Matrix metalloproteases; a potential role in the pathogenesis of the acute respiratory distress syndrome. In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg, pp 287 – 300

12. Warner RL, Beltran L, Younkin EM, et al (2001) Role of stromelysin 1 and gelatinase B in experimental acute lung injury. Am J Respir Cell Mol Biol 24:537 – 544

13. Pugin J, Verghese G, Widmer MC, Matthay MA (1999) The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 27:304 – 312

14. Fligiel S, Standiford T, Fligiel H, et al (2006) Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury. Hum Pathol 37:422 – 430

15. McAuley D, Frank J, Fang X, Matthay M (2004) Clinically relevant concentrations of beta2- adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury.

Crit Care Med 32:1470 – 1476

16. Perkins G, McAuley D, Gao F, Thickett D (2004) Intravenous salbutamol reduced alveolar- capillary permeability and extra-vascular lung water in ARDS. Thorax 59 (Suppl II):T1 (abst) 17. Dudek SM, Garcia JG (2001) Cytoskeletal regulation of pulmonary vascular permeability. J

Appl Physiol 91:1487 – 1500

(12)

18. Weitz-Schmidt G WK, Brinkmann V, et al (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7:687 – 692

19. Dichtl W DJ, Frick M, Alber HF, et al (2003) HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arteri- oscler Thromb Vasc Biol 23:58 – 63

20. Sen- Banerjee S, Mir S, Lin Z, et al (2005) Kruppel-Like Factor 2 as a Novel Mediator of Statin Effects in Endothelial Cells. Circulation 112:720 – 726

21. Martin G, Duez H, Blanquart C, et al (2001) Statin-induced inhibition of the Rho-signaling pathway activates PPAR´a and induces HDL apoA-I. J Clin Invest 107:1423 – 1432

22. Senokuchi T, Matsumura T, Sakai M, et al (2005) Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small g protein-p38 MAPK pathway. J Biol Chem 280:6627 – 6633

23. Jacobson JR, Barnard JW, Grigoryev DN, et al (2005) Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 288:L1026 – 1032

24. Pirat A, Zeyneloglu P, Aldemir D, et al (2006) Pretreatment with simvastatin reduces lung injury related to intestinal ischemia-reperfusion in rats. Anesth Analg 102:225 – 232 25. Naidu BV, Woolley SM, Farivar AS, Thomas R, Fraga C, Mulligan MS (2003) Simvastatin ame-

liorates injury in an experimental model of lung ischemia-reperfusion. J Thorac Cardiovasc Surg 126:482 – 489

26. Kaneider NC, Reinisch CM, Dunzendorfer S, Meierhofer C, Djanani A, Wiedermann CJ (2001) Induction of apoptosis and inhibition of migration of inflammatory and vascular wall cells by cerivastatin. Atherosclerosis 158:23 – 33

27. Weber C, Erl W, Weber KS, Weber PC (1997) HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 30:1212 – 1217

28. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E (1999) Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 100:230 – 235

29. Diomede L, Albani D, Sottocorno M, et al (2001) In vivo Anti-Inflammatory Effect of Statins Is Mediated by Nonsterol Mevalonate Products. Arterioscler Thromb Vasc Biol 21:1327 – 1332 30. Rezaie-Majd A, Maca T, Bucek R, et al (2002) Simvastatin reduces expression of cytokines

interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 22:1194 – 1199 31. Steiner S, Speidl WS, Pleiner J, et al (2005) Simvastatin blunts endotoxin-induced tissue fac-

tor in vivo. Circulation 111:1841 – 1846

32. Li JJ, Wang Y, Nie SP, Zhang CY, et al (2007) Reduction of C-reactive protein by a single 80 mg of simvastatin in patients with unstable angina. Clin Chim Acta 376:163 – 167

33. Nagashima H, Aoka Y, Sakomura Y, et al (2002) A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall. J Vasc Surg 36:158 – 163

34. Aikawa M, Rabkin E, Sugiyama S, et al (2001) An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 103:276 – 283

35. Koh K, Ahn J, Jin D, et al (2004) Comparative effects of statin and fibrate on nitric oxide bio- activity and matrix metalloproteinase in hyperlipidemia. Int J Cardiol 97:239 – 244

36. Wassmann S, Laufs U, Müller K, et al (2002) Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 22:300 – 305

37. Laufs U, La Fata V, Liao J (1997) Inhibition of 3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 272:31725 – 31729

38. Jacobson JR, Dudek SM, Konstantin G, et al (2004) Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin. Am J Respir Cell Mol Biol 30:662 – 670

39. Kario K, Matsuo T, Hoshide S (1999) Lipid-lowering therapy corrects endothelial cell dysfunction in a short time but does not affect hypercoagulable state even after long-term use in hyperlipidemic patients. Blood Coagul Fibrinolysis 10:269 – 276

(13)

40. Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA (2003) Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 285:L20 – 28

41. Bourcier T, Libby P (2000) Expression by human vascular smooth muscle and endothelial cells HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1. arterioscler.

Thromb Vasc Biol 20:556 – 562

42. Ware LB, Matthay MA (2001) Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 163:1376 – 1383

43. Hayden JM, Swartfiguer J, Szelinger S, et al (2005) Lysophosphatidylcholine stimulation of alveolar epithelial cell interleukin-8 production and neutrophil chemotaxis is inhibited by statin treatment. Proc Am Thorac Soc 2:A72 (abst)

44. Merx MW, Liehn EA, Janssens U, et al (2004) HMG-CoA reductase inhibitor simvastatin pro- foundly improves survival in a murine model of sepsis. Circulation 109:2560 – 2565 45. Almog Y, Shefer A, Novack V, et al (2004) Prior statin therapy is associated with a decreased

rate of severe sepsis. Circulation 110:880 – 885

46. Liappis AP, Kan VL, Rochester CG, Simon GL (2001) The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 33:1352 – 1357

47. Kruger P FK, Cook D, Jones M, Nimmo G (2006) Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med 32:75 – 79

48. Hackam DG MM, Li P, Redelmeier DA (2006) Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet 367:413 – 418

49. British Medical Association and Royal Pharmaceutical Society of Great Britain (2006) British National Formulary. Pharmaceutical Press, London

50. de Lemos JA, Blazing MA, Wiviott SD, et al (2004) Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes JAMA 292:1307 – 1316