Subacute exposure to moderate hypoxia can promote pulmonary edema formation. The tachykinins, a family of pro-inflammatory neuropeptides, have been implicated in the pathogenesis of pulmonary edema in some settings, including the pulmonary vascular leak associated with exposure to hypoxia. The effects of hypoxia on tachykinin receptor and peptide expression in the lung, however, remain poorly understood. We hypothesized that subacute exposure to moderate hypoxia increases lung NK-1 receptor expression as well as lung substance P levels. We tested this hypothesis by exposing weanling Sprague-Dawley rats to hypobaric hypoxia (Pbaro = 0.5 atm) for 0, 24, 48, or 72 hours. Hypoxia led to time-dependent increases in lung NK-1 receptor mRNA expression and lung NK-1 receptor protein levels at 48 and 72 hours of exposure (p<0.05). Immunohistochemistry and in situ NK1 receptor labeling with substance P-conjugated fluorescent nanocrystals demonstrated that hypoxia increased NK1 expression primarily in the pulmonary microvasculature and in alveolar macrophages. Hypoxia also led to increases in lung substance P levels by 48 and 72 hours (p < 0.05) but led to a decrease in preprotachykinin mRNA levels (p < 0.05). We conclude that subacute exposure to moderate hypoxia up-regulates lung NK-1 receptor expression and lung substance P peptide levels primarily in the lung microvasculature. We speculate that this effect may contribute to the formation of pulmonary edema in the setting of regional or environmental hypoxia.