N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors widely distributed in the central nervous system, and have been extensively investigated for their roles in embryonic development, synaptic plasticity and neuroexcitoxicity. Their functions in the peripheral nervous system and non-neural tissues have caught much attention recently. Over-activation of NMDA receptors induces excitotoxic lung injury. But the endogenous cell types in the lungs that express NMDA receptors remains elusive and the molecular mechanism underlies NMDA-induced lung injury has not been fully characterized. In this work, we reported that functional NMDA receptors were expressed in alveolar type II cells in the lungs. Over-activation of these receptors led to down-regulation of pulmonary surfactants synthesis. We further demonstrated that decreased cellular choline-phosphate cytidylyltransferase alpha expression induced by NMDA treatment accounted for the decreased pulmonary surfactants synthesis. Our results provided important clues for treatment of glutamate lung injury by modulating pulmonary surfactants system.Glutamate is one of the major excitatory neurotransmitters in the central nervous system (CNS). Acting through its receptors, glutamate plays important roles under many physiological and pathophysiological conditions, including embryonic development, synaptic plasticity and neuroexcitoxicity. Several classes of glutamate receptors, widely distributed throughout the CNS, have been identified and categorized into three subtypes of ionotropic receptors [N-methyld-aspartate (NMDA), AMPA and kainate receptors], and a family of heterogeneous G-protein-coupled metabotropic receptors. The NMDA receptors have been the focus of much attention because of their implication in learning and memory, as well as in neuronal cell injury and death under acute conditions such as head injury, stroke and epileptic seizures; and in chronic neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and AIDS dementia [1].However, the existence and importance of NMDA receptors in the peripheral nervous system and in non-neural tissues have caught much attention recently. Functional NMDA receptors have been identified in many cells outside of CNS, such as cells in liver, kidney, pancreas, testis, skin and lungs, which suggest that glutamate signalling in these cells may play important roles under certain physiological or pathophysiological conditions [2].The first indication of glutamate signalling in the lungs came with the observation that glutamate receptor agonist NMDA could induce acute lung injury in an in vitro model [3]. Our recent work also showed that NMDA receptor mediated glutamate lung injury in mice [4][5][6]. Said et al. demonstrated that endogenous glutamate toxicity was a major cause of oxidant lung injury [7]. Although previous investigation showed that NMDA receptors were expressed in airways, in gas-exchange zone of lungs and in the alve...