Aspirin has been demonstrated to be effective in inhibiting COX-2 and PGE2 in Alveolar macrophages (AMs). However,the mechanisms have not been fully understood. In the presentstudy, we found that pretreatment with aspirin inhibitedLPS-induced COX-2 and PGE2 upregulation, IκBα degradation,NFκB activation and the increase of PKC activity, but elevatedLPS-induced the decrease of PTP activity. The PKC inhibitorcalphostin C dramatically reduced the COX-2 mRNA andPGE2 levels, but the PTP inhibitor peroxovanadium (POV)significantly increased the COX-2 mRNA and PGE2 levels. Furthermore, the PTP inhibitor mitigated the inhibitory effectof aspirin on COX-2 and PGE2 upregulation and NF-κBactivation, whereas the PKC inhibitor enhanced the inhibitoryeffects of aspirin on the production of COX-2 and PGE2. Ourdata indicate a novel mechanism by which aspirin acts as apotent anti-inflammatory agent in alveolus macrophages andALI.