Abstract Rationale Acute respiratory distress syndrome (ARDS) lacks FDA-approved therapies and is associated with high mortality, particularly in older patients. Preclinical ARDS studies rarely assess age-dependent therapeutic responses. We previously showed that inhibition of P-selectin/PSGL-1 interactions with a novel tandem PSGL-1 immunoglobulin fusion molecule (TSGL-Ig) attenuates lung inflammation in murine models of ARDS. This study investigates the effect of age on TSGL-Ig efficacy in an LPS-induced rat model of lung injury. Methods Male and female Sprague-Dawley rats aged 6 weeks (young) or 12 months (old) received intratracheal LPS followed by intravenous TSGL-Ig or PBS 10 minutes post-LPS. After 24 hours, bronchoalveolar lavage (BAL) fluid was analyzed for total cell counts (CC) and protein concentration. Lungs were harvested for histologic analysis (H&E staining) and Western blot. Results TSGL-Ig significantly attenuated LPS-induced lung injury in young but not in old rats, reflected by reduced BAL CC (P = 0.007 young vs. P = 0.075 old) and BAL protein (P = 0.002 young vs. P = 0.11 old). Histologic injury and polymorphonuclear cell infiltration were significantly reduced in young rats treated with TSGL-Ig (P = 0.001 young vs. P = 0.12 old). Older rats exhibited higher baseline BAL CC (P = 0.0007) but similar BAL protein (P = 0.12) compared to young rats. Conclusions TSGL-Ig significantly mitigates LPS-induced lung injury in an age-dependent manner favoring young but not aged rats. Although there was a trend to efficacy in aged rats, these results suggest the increased oxidative stress and altered innate immune function known to be associated with aging may reduce therapeutic responsiveness requiring dosing considerations. This abstract is funded by: NIH
Bime et al. (Fri,) studied this question.