The effect of SOD mimetic treatment on interstitial macrophage accumulation in chronic hypoxic pulmonary hypertension

Thi-Tina Nguyen^1,2, Caitlin Lewis^1,2, Janelle Posey^1,2, Rebecca Oberley-Deegan³, Cassidy Delaney^1,2, Samuel Burciaga^1,2, Eva Nozik^1,2

¹Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
²Department of Cardiovascular Pulmonary Research Laboratories, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
³Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha,
Nebraska, USA

Pulmonary hypertension (PH) is a fatal disease defined by elevated pulmonary artery pressure.
Inflammation and oxidative stress are recognized as key components of PH pathophysiology. The
inflammatory response includes recruitment of interstitial macrophages (IMs). These IMs undergo
reprogramming to drive inflammation and resolution, and they can be subdivided into three
subtypes, IM1, IM2, and IM3. Mouse strains with low levels of the key vascular antioxidant enzyme,
extracellular superoxide dismutase (EC-SOD), have worsened chronic hypoxia-induced PH and
increased IM accumulation at 4 days post-hypoxia. An EC-SOD mimetic drug Mn(III)tetrakis(Nethylpyridinium-2-yl)porphyrin, administered throughout chronic hypoxia, protects against PH, but
its effects on IM accumulation is unknown. Therefore, we hypothesize that SOD mimetic
treatment prevents IM accumulation in hypoxia. To model chronic hypoxic PH, mice were
exposed to four days of hypoxia at 385 torr, equivalent to 18,000 ft elevation. A single dose of
SOD mimetic treatment was administered subcutaneously prior to exposure. We found that mice
exposed to hypoxia had an increase in total IMs. With the addition of SOD mimetic treatment,
there was a reduction in total IM accumulation compared to the hypoxia group. SOD mimetic
treatment also attenuated IM1 and IM2 subset accumulation while IM3 remained unchanged. This
data suggests that the extracellular redox environment, impacted by EC-SOD contributes to
hypoxia induced IM accumulation. Future studies will assess if the protection of the SOD mimetic
is mediated by its impact on IM accumulation or reprogramming.