Adiponectin, an adipokine, accumulated in lung system via T-cadherin after allergens/ozone challenge. However, the roles of adiponectin on lung pathologies were controversial. Here we reported that adiponectin stimulated expression of inflammatory proteins, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), and production of ROS in human alveolar type II A549 cells. AdipoR1/2 involved in adiponectin-activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria, which further promoted intracellular reactive oxygen species (ROS) accumulation. Protein kinase C (PKC) may involve in adiponectin-activated NADPH oxidase. Similarly, p300 phosphorylation and histone H4 acetylation occurred in adiponectin-challenged A549 cells. Moreover, adiponectin-upregulated cPLA2 and COX-2 expression was significantly abrogated by ROS scavenger (N-acetylcysteine) or the inhibitors of NADPH oxidase (apocynin), mitochondria electron transport chain (rotenone), PKC (Ro31-8220, Gö-6976 and rottlerin) and p300 (garcinol). Briefly, we reported that adiponectin stimulated cPLA2 and COX-2 expression via adipoR1/2-dependent activation of PKC/NADPH oxidase/mitochondria resulting in ROS accumulation, p300 phosphorylation and histone H4 acetylation. These results suggested that adiponectin promoted lung inflammation resulting in exacerbation of pulmonary diseases via upregulating cPLA2 and COX-2 expression together with intracellular ROS production. Understanding the adiponectin signaling pathways on regulating cPLA2 and COX-2 may help develop therapeutic strategies on pulmonary diseases.