433 - Adrenomedullin Overexpression Attenuates Experimental Bronchopulmonary dysplasia and Pulmonary Hypertension in Mice

Poster Number: 433
Publication Number: 433.430

Amrit K. Shrestha, Baylor College of Medicine, Houston, TX, United States; Poonam Sarkar, Baylor College of Medicine, Houston, TX, United States; M. Waleed Gaber, Baylor College of Medicine, Houston, TX, United States; Roberto Barrios, Weill Cornell Medicine, Houston, TX, United States; Binoy Shivanna, Baylor College of Medicine, Houston, TX, United States

Background: Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) or BPD-PH is a lung disease of infants with significant long-term morbidity. Adrenomedullin (Adm) is an angiogenic peptide that signals through calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2 (RAMP2). Adm deficiency potentiates hyperoxia-induced experimental BPD-PH in mice; however, whether Adm overexpression can mitigate this lung disease is unclear.

Objective: To test the hypothesis that Adm overexpression attenuates hyperoxia-induced murine experimental BPD-PH.

Design/Methods: We used a novel transgenic mouse that overexpresses Adm globally (Admhi/hi mice) to test our hypothesis. One-day-old Admhi/hi mice or their wild-type littermates (Adm+/+ mice) were exposed to hyperoxia (FiO2 70%) for 14 d and allowed to recover in normoxia (FiO2 21%) for an additional 14 d. A separate group of Adm+/+ mice or Admhi/hi mice were maintained in normoxia for 28 d. On postnatal day (P) 14, we harvested the lungs to determine the extent of Adm expression, inflammation, oxidative stress, and apoptosis.  On P28, we determined lung development by morphometry and quantified indices of PH (pulmonary acceleration time [PAT], RV ejection time [ET], PAT/ET, and RV systolic pressure [RVSP]) by echocardiography.

Results: The lung Adm mRNA levels were three-fold higher in Admhi/hi mice compared with Adm+/+ mice. On P14, hyperoxia-exposed Adm+/+ mice demonstrated increased lung inflammation, oxidative stress, and apoptosis. Additionally, on P28, Adm+/+ mice exposed to neonatal hyperoxia exhibited decreased alveolarization or alveolar simplification, as evident by decreased radial alveolar counts and increased mean linear intercepts compared with Adm+/+ mice exposed to normoxia. Further, Adm+/+ mice exposed to neonatal hyperoxia displayed decreased PAT and PAT/ET ratio and increased RVSP, indicating that neonatal hyperoxia exposure causes PH. However, Adm overexpression attenuated experimental BPD-PH, as evident by the decreased extent of hyperoxia-induced lung inflammation, apoptosis, alveolar simplification, and PH in Admhi/hi mice than in Adm+/+ mice. Conclusion(s): Adm overexpression attenuates hyperoxia-induced murine experimental BPD-PH. Our results indicate that Adm is a potential therapeutic agent to improve the prognosis of BPD-PH in preterm infants.