The aim of this study was to investigate the effect of costunolide (CS) and dehydrocostuslactone (DCE) a well-known sesquiterpene lactones contained in many plants, in a model of lung injury induced by carrageenan administration in the mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and increased production of tumour necrosis factor α (TNF-α). All parameters of inflammation were attenuated by CS and DCE (15 mg/kg 10% DMSO i.p.) administered 1 h before carrageenan. Carrageenan induced an up regulation of the intracellular adhesion molecules-1 (ICAM-1) and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) (PAR) as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PAR was reduced by CS and DCE. Additionally we show that this inflammatory events were associated with NF-κB and STAT3 activation and these sesquiterpenes down-regulated it. Taken together, ours results clearly shown that CS and DCE may offer a novel therapeutic approach for the management of inflammatory diseases.