Effects of Inhaled Erythropoietin on Canine Post‐pneumonectomy Compensatory Lung Growth

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Paracrine erythropoietin (Epo) signaling via its receptor (EpoR) recruits endothelial progenitor cells and promotes angiogenesis. Epo‐EpoR axis is upregulated during canine post‐pneumonectomy (PNX) compensatory lung growth (CLG). To determine whether exogenous Epo augments endogenous CLG, adult male canines (age 1 year, 25.1± 3.4 kg, mean±SD) underwent right PNX and received either recombinant human Epo (100 units/kg) encapsulated within poly‐lactic‐co‐glycolic acid (PLGA) nanoparticles (NPs, 0.5 mg/kg) or empty NPs (n=4 animals each), suspended in phosphate buffered saline, nebulized (4μm droplets) and delivered via a previously constructed permanent tracheal stoma. Treatment was repeated weekly for 14 weeks. High resolution CT (HRCT) was performed at two transpulmonary pressures (10 and 30 cmH 2 O) and lung function was measured using established techniques under anesthesia pre‐PNX and post‐PNX following treatment. HRCT images were analyzed to quantify lobar air and tissue volumes, fractional tissue volume (FTV), parenchymal strain magnitude along 3D coordinate axes, principal strains and shear distortion using established deformation analysis. The remaining lobes were fixed at 25 cm H 2 O airway pressure for morphometric analysis. Compared to control treatment, Epo delivery increased serum Epo concentration by 6–13% (p<0.05) without increasing systemic hematocrit. Epo delivery selectively increased the magnitude and reduced the coefficient of variation of in vivo FTV (10–20%, p<0.05) of the remaining lobes without altering lobar air and tissue volumes, principal strains or shear distortion measured by HRCT. Epo treatment increased the prevalence of alveolar double capillary profiles measured at postmortem by 12–28% (p=0.06), indicating mild enhancement of new capillary formation. However, resting lung diffusing capacity (DL CO ), pulmonary blood flow, lung compliance, and postmortem extravascular alveolar tissue volume and alveolar surface area, were not significantly different from control. We conclude that targeted inhalational delivery of exogenous Epo improved post‐PNX pulmonary microvascular blood volume distribution and modestly augmented alveolar angiogenesis. Treatment did not significantly alter extravascular alveolar tissue growth, regional lung mechanics or physiological function measured at rest. Support or Funding Information Supported by NHLBI R01 HL40070 and U01 HL111146.

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