LAUSR

Objective: ARDS carries a mortality rate >30% due to lack of early detection tools, inability to identify patients at risk for progression, and limited therapies. Exposure of adult rats to hyperoxia (100% O2) is a well-established model of human ARDS. Adult rats exposed to 100% O2 display the first clinical evidence of lung injury after >40 hours (hrs) of exposure with worsening at 60 hrs, and death by 72 hrs. On the other hand, adult rats exposed to 60% O2 for up to 7 days show no sign of injury. However, when adult rats are pre-exposed to 60% O2 for 7 days (H-S), they become more susceptible to hyperoxia-induced ARDS as evidenced by a decrease in their subsequent survival time in 100% O2 environment. This study aims to evaluate the lung uptake of 99mTc-HMPAO and 99mTc-DU, reflecting tissue redox status and cell death, respectively, in H-S rats before and after exposure to 100% O2 to determine their ability to track susceptibility of H-S rats and to elucidate underlying mechanisms. Methods: Adult Sprague-Dawley rats were exposed to either room air (normoxia), 60% O2 for 7 days (H-S), 100% O2 for 24 hr (24-hr hyperoxia), or H-S followed by 24 hrs of hyperoxia (H-S+24). Rats were then anesthetized and imaged using either 99mTc-DU or 99mTc-HMPAO. In vivo scintigraphy images were acquired 20 min post i.v. injection and lung uptake of these biomakers was determined from the images. Pulmonary vascular endothelial filtration coefficient ( Kf ) as a measure of pulmonary vascular permeability was also measured. Results: Lung HMPAO and DU uptake increased by 50% and 26%, respectively, in H-S rats compared to uptake in the lungs of normoxia rats. Exposure of H-S rats to 24 hrs of 100% O2 (H-S+24) increased DU uptake by 150% compared to uptake in H-S rats, but had no significant effect on HMPAO lung uptake. HMPAO lung uptake was 134% higher in 24-hr hyperoxia rats compared to normoxia rats, whereas DU lung uptake was not different between 24-hr hyperoxia and normoxia rats. Kf increased by 178% in the lungs of H-S rats compared to that in lungs of normoxia rats. There was no significant difference in Kf between 24-hr hyperoxia rats and weight-matched normoxia rats. D iscussion: Lung uptake of 99mTc-HMPAO and 99mTc-DU is differentially altered between normoxia and H-S rats, which is amplified following exposure to 100% O2 for 24 hrs (H-S+24 vs 24-h hyperoxia). The increase in DU lung uptake, a measure of cell death, is consistent with the increase in Kf . The susceptibility of H-S rats to hyperoxia-induced lung injury could be due to the increase in Kf . Overall, these results suggest the potential utility of 99mTc-HMPAO and 99mTc-DU imaging for identifying those hosts that are more or less susceptible to progression to severe ARDS at a mild symptoms of lung injury. We thank Sushma Kaul for her help with the experiments. This work was supported by NIH 2R15HL129209-02 (Audi, Clough, Jacobs), 5R01HL152712 (Zhao), and VA Merit Review Award BX001681 (Jacobs, Audi, Clough). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.