Genetic variation in surfactant protein-A2 alters responses to ozone

BACKGROUND: Increased exposure to Ozone (O(3)) is associated with adverse health effects in individuals afflicted with respiratory diseases. Surfactant protein-A (SP-A), encoded by SP-A1 and SP-A2, is the largest protein component in pulmonary surfactant and is functionally impaired by O(3)-oxidation. OBJECTIVE: We used humanized SP-A2 transgenic mice with allelic variation corresponding to a glutamine (Q) to lysine (K) amino acid substitution at position 223 in the lectin domain to determine the impact of this genetic variation in regards to O(3) exposure. METHODS: Mice were exposed to 2ppm O(3) or Filtered Air (FA) for 3 hours and 24 hrs post-challenge pulmonary function tests and other parameters associated with inflammation were assessed in the bronchoalveolar lavage (BAL) fluid and lung tissue. Additionally, mouse tracheal epithelial cells were cultured and TEER measurements recorded for each genotype to determine baseline epithelial integrity. RESULTS: Compared to FA, O(3) exposure led to significantly increased sensitivity to methacholine challenge in all groups of mice. SP-A2 223Q variant mice were significantly protected from O(3)-induced AHR compared to SP-A(-/-) and SP-A2 223K mice. Neutrophilia was observed in all genotypes of mice post O(3)-exposure, however, SP-A2 223Q mice had a significantly lower percentage of neutrophils compared to SP-A(-/-) mice. Albumin levels in BAL were unchanged in O(3)-exposed SP-A2 223Q mice compared to their FA controls, while levels were significantly increased in all other genotypes of O(3)-exposed mice. SP-A 223Q MTECS has significant higher TEER values than all other genotypes, and WT MTECS has significantly higher TEER than the SP-A KO and SP-A 223K MTECS. SIGNIFICANCE: Taken together, our study suggests that expression of a glutamine (Q) as position 223 in SP-A2, as opposed to expression of lysine (K), is more protective in acute exposures to ozone and results in attenuated O(3)-induced AHR, neutrophilia, and vascular permeability.