Altintas and colleagues made a nice contribution on the field of acute lung injury (ALI), showing that pretreatment with simvastatin attenuates lung injury induced by oleic acid and endotoxin in mice.¹

Although the authors cited a few papers to state that “the available studies on statins in ALI are limited,”¹ we believe that the evidence regarding the beneficial role of statins against ALI is growing. For example, our colleagues could mention another recent article that explored the impact of statin administration on the development of ALI induced by high-stretch mechanical ventilation.² Indeed, by implementing an isolated perfused mechanically ventilated rabbit lung model, our research team demonstrated that pretreatment with atorvastatin improves alveolar capillary permeability and hemodynamics, and thus attenuates ventilator-induced lung injury (VILI).² Our results were later confirmed by another contribution, which also noted that pretreatment with simvastatin protects against VILI in an in vivo murine model.³ On the basis of the above 2 articles^2,3 it could be argued that administration of statins protects against VILI from the acute until the late phases of lung injury, through variable (not only anti-inflammatory/anti-oxidative) mechanisms.⁴ Additional contributions revealing the protective role of statins against ALI induced by other stimuli, such as cotton smoke inhalation or irradiation, could also be retrieved and cited.⁵

On the other hand, the histological finding of Altintas and colleagues that animal lungs in the statin group without injurious stimulus showed vascular dilatation and stasis is interesting.¹ In our above-mentioned study we also found that the statin group without injurious stimulus had more (albeit statistically nonsignificant) intra-alveolar hemorrhage than the control (ie, no statin and non-injurious stimulus) group.² This finding did not correlate with any difference in pulmonary artery pressure between these 2 (ie, statin and non-injurious stimulus vs no statin and non-injurious stimulus) groups.² We agree with the authors that the clinical importance of this histological finding may need further investigation.

In conclusion, on the basis of the rapidly accumulating evidence, we share the concluding comment of our colleagues that clinical trials regarding the potential prophylactic value of statin administration in the prevention of ALI seem to be fully justified.

• © 2012 by Daedalus Enterprises Inc.

The authors respond:

331 332

We have read with interest the encouraging constructive comments of Siempos and colleagues about our paper “Long-term simvastatin attenuates lung injury and oxidative stress in murine acute lung injury models induced by oleic acid and endotoxin,” which was published in Respiratory Care.¹

They especially focused on the finding of vascular dilatation and stasis in animal lungs in the statin pretreatment group without injurious stimulus. The clinical importance of this histological finding may need to be discussed. We have some “unpublished data” that supports the beneficial effects of simvastatin even on healthy animals (Fig. 1).

• Download figure
• Open in new tab
• Download powerpoint

Fig. 1.

Mesenteric artery flow indices in saline, endotoxin, and oleic acid-treated groups. Mesenteric artery flow index increased in mice after endotoxin injection, whereas it decreased in mice after oleic acid injection, as compared to the control group, which received saline (P = .028 and P = .009, respectively). Pretreatment with simvastatin resulted in higher mesenteric flow indices in the control and oleic acid groups.

An interesting and very important finding was the higher mesenteric artery indices in mice that received only simvastatin (2 mg/kg/d in a volume of 10 mL/kg, for 15 d), compared to those that received only saline injections. This unknown vasodilatory action of simvastatin and also the observed vascular dilatation and stasis in lungs (in the manuscript) can be explained with some valuable previous works. It was demonstrated that statins up-regulate endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production by increasing eNOS expression (and eNOS mRNA stability) after hypoxic conditions and even under baseline conditions.^2,3 The ability of statins to exert this effect on eNOS expression was independent of cholesterol concentrations, which revealed one of the most significant pleiotropic effects of acute statin therapy.⁴ This increase in physiological, baseline NO production may be the explanation of these beneficial effects of simvastatin.

We hope the vasodilatory effect of chronic simvastatin therapy in healthy animals will also be supported with clinical studies in humans.

References

1. 1.
   1. Altintas ND,
   2. Atilla P,
   3. Iskit AB,
   4. Topeli A

   . Long-term simvastatin attenuates lung injury and oxidative stress in murine acute lung injury models induced by oleic acid and endotoxin. Respir Care 2011;56(8):1156–1163.
2. 2.
   1. Laufs U,
   2. La Fata V,
   3. Liao J.K

   . Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated downregulation of endothelial nitric oxide synthase. J Biol Chem 1997;272(50):31725–31729.
3. 3.
   1. Laufs U,
   2. La Fata V,
   3. Plutzky J,
   4. Liao J.K

   . Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97(12):1129–1135.
4. 4.
   1. Kureishi Y,
   2. Luo Z,
   3. Shiojima I,
   4. Bialik A,
   5. Fulton D,
   6. Lefer DJ,
   7. et al

   . The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis innormocholesterolemic animals. Nat Med 2000;6(9):1004–1010. Erratum in: Nat Med 2001;7(1):129.