Protective effects of rosuvastatin in a rat model of lung contusion: Stimulation of the cyclooxygenase 2-prostaglandin E-2 pathway.
BACKGROUND
Lung contusion, which can occur in patients with blunt thoracic trauma, is a leading risk factor for development of acute lung injury (ALI) and acute respiratory distress syndrome. Statins are lipid-lowering drugs with many beneficial antiinflammatory and antioxidative effects. We therefore hypothesized that the administration of statins immediately after trauma will inhibit the production of inflammatory mediators, and thereby alleviate the severity of lung injury.


METHODS
A model of blunt chest injury in rat was employed. The effects of statins (rosuvastatin) and cyclooxygenase-2 (COX-2) inhibitors (meloxicam) on ALI were assessed by measuring inflammatory mediator levels in the serum and in the bronchoalveolar space. Animals were killed at the end of day 3. Histologic evaluation of lung tissue was performed to confirm the presence and severity of lung contusion as well as the effects of statins, nonsteroidal antiinflammatory drugs, and their combination.


RESULTS
Administration of meloxicam after lung contusion decreased the amount of neutrophil infiltration; however, marked hemorrhage and edema were still noticed. Administration of rosuvastatin decreased significantly cytokine levels that were increased after the blunt chest trauma. Rosuvastatin increased the expression of inducible nitric oxide (iNOS), COX-2, heme oxygenase-1 (HO-1), and prostaglandin E2 (PGE-2) in the bronchoalveolar lavage fluid of the rat contused lungs. Coadministration of meloxicam prevented these changes.


CONCLUSIONS
Rosuvastatin treatment after lung contusion attenuated several features of ALI. The enhanced activity of iNOS, COX-2, and HO-1 in the lung may reflect the advent of protective processes that took place in the contused lung. To our knowledge, this is the first demonstration that prostaglandin pathways play an essential role in the effects of statins in lung injury.
Pre-Clinical Research Laboratory and Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: dolkarto@gmail.com.
Oleg
O
Dolkart
Pre-Clinical Research Laboratory and Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Eyal
E
Amar
Pre-Clinical Research Laboratory and Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Shiran
S
Shapira
Pathology Institute, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Sylvia
S
Marmor
Pre-Clinical Research Laboratory and Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Eli L
EL
Steinberg
Pre-Clinical Research Laboratory and Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Avi A
AA
Weinbroum
D055371:Acute Lung Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003288:Contusions / Q000150:complications; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005464:Fluorobenzenes / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology; D008297:Male; D000077239:Meloxicam; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013843:Thiazines; D013844:Thiazoles
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; D000068718:Rosuvastatin Calcium; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone; D000077239:Meloxicam