ABSTRACT
Lung is one of the vital organs which is affected during the sequential development of multi-organ dysfunction in sepsis. The purpose of the present study was to examine whether combined treatment with atorvastatin and imipenem could attenuate sepsis-induced lung injury in mice. Sepsis was induced by caecal ligation and puncture. Lung injury was assessed by the presence of lung edema, increased vascular permeability, increased inflammatory cell infiltration and cytokine levels in broncho-alveolar lavage fluid (BALF). Treatment with atorvastatin along with imipenem reduced the lung bacterial load and pro-inflammatory cytokines (IL-1ß and TNFα) level in BALF. The markers of pulmonary edema such as microvascular leakage and wet-dry weight ratio were also attenuated. This was further confirmed by the reduced activity of MPO and ICAM-1 mRNA expression, indicating the lesser infiltration and adhesion of inflammatory cells to the lungs. Again, expression of mRNA and protein level of iNOS in lungs was also reduced in the combined treatment group. Based on the above findings it can be concluded that, combined treatment with atorvastatin and imipenem dampened the inflammatory response and reduced the bacterial load, thus seems to have promising therapeutic potential in sepsis-induced lung injury in mice.
Subject(s)
Acute Lung Injury/metabolism , Atorvastatin/administration & dosage , Bacterial Load/drug effects , Imipenem/administration & dosage , Inflammation Mediators/metabolism , Sepsis/metabolism , Acute Lung Injury/drug therapy , Acute Lung Injury/microbiology , Animals , Bacterial Load/physiology , Drug Therapy, Combination , Inflammation Mediators/antagonists & inhibitors , Male , Mice , Sepsis/drug therapy , Sepsis/microbiologyABSTRACT
The purpose of the study was to examine whether arachidonic acid inhibits vascular Na(+)-K(+)-ATPase in pulmonary vasculature and if so, what are the mechanisms involved. Functional Na(+)-K(+)-ATPase activity was studied in terms of K(+)-induced relaxation in sheep pulmonary arterial rings contracted with K(+)-free solution and 5-HT. Arachidonic acid (10-100 µM) caused concentration-dependent inhibition of KCl-induced relaxations and also increased basal arterial tone. Cytochrome P-450 inhibitor, 17-octadecynoic acid (17-ODYA) completely reversed the arachidonic acid (30 µM)-induced inhibition of KCl relaxation. Further, in the presence of HET0016, a selective blocker of 20-hydroxyeicosatetraenoic acid (20-HETE), arachidonic acid-induced inhibition of KCl relaxation was not evident. Accordingly, 20-HETE, a cytochrome P-450 metabolite of arachidonic acid, also significantly attenuated KCl-induced relaxations. Norhydihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, however, partially restored the relaxation to K(+), impaired in the presence of arachidonic acid (30 µM). On the other hand, cyclooxygenase inhibitor indomethacin failed to reverse the inhibitory effect of arachidonic acid on KCl-induced relaxation. Staurosporin, a protein kinase C inhibitor, completely reversed the inhibitory effect of arachidonic acid and 20-HETE on K(+)-induced relaxation. In conclusion, the results suggest that 20-HETE, a cytochrome P-450 metabolite of arachidonic acid has a predominant role in the inhibition of functional Na(+)-K(+)-ATPase activity in the sheep pulmonary artery, while the lipooxygenase pathway has a secondary role. It is also evident that protein kinase C is involved in the inhibition of Na(+)-K(+)-ATPase by arachidonic acid/20-HETE in sheep pulmonary artery.
