434 - Early Versus Late Caffeine and/or Non-Steroidal Anti-Inflammatory Drug (NSAIDs) on Biomarkers of Lung Inflammation in Neonatal Rats Exposed to Intermittent Hypoxia

Poster Number: 434
Publication Number: 434.430

Kulsajan S. Bhatia, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States; Charles Cai, SUNY Downstate, BROOKLYN, NY, United States; Jacob Aranda, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States; Stephen J. Wadowski, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States; Kay Beharry, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States

Background:
Immature respiratory control, prematurity, intermittent hypoxia (IH), and resulting inflammation, contribute to the development of chronic lung disease in preterm infants.  Early caffeine therapy has been shown to be associated with reduced lung inflammation.  Cyclooxygenase inhibitors, such as ibuprofen have also been shown to improve lung mechanics in animal models.

Objective:
We tested the hypotheses that: 1) Caffeine and NSAID co-treatment has synergistic benefits for reducing IH-induced inflammation in the neonatal rat lungs, and 2) early postnatal treatment during IH is more beneficial than late treatment during reperfusion/reoxygenation.

Design/Methods: Newborn rats (n=18/group) were exposed to brief hypoxia (12% O2) during hyperoxia (50% O2) from birth (P0) to P14) or room air (RA). For early, the pups were administered: 1) a single daily IP injection of caffeine citrate (Cafcit, 10 mg/kg loading on P0, followed by 5 mg/kg maintenance from P1-P14); 2) ketorolac topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Neoprofen, 10 mg/kg loading dose on P0 followed by 5 mg/kg/day on P1 and P2); 4) caffeine+ketorolac co-treatment; 5) caffeine+ibuprofen co-treatment; or 6) equivalent volume saline.  On P14, animals were placed in RA with no further treatment.  For late, the pups received similar treatments from P15-P17 (ibuprofen) or P15-P21 (caffeine and/or ketorolac).  At P21, lungs (n=6/group) were assessed for growth and biomarkers of inflammation (IL-1, TNFα, IL-6, IL-10).

Results: Neonatal IH resulted in reduced weight accretion and lung/body weight ratios in both early and late groups. Early ibuprofen was beneficial for preserving body weight accretion and lung/body weight ratios.  All late treatments were beneficial. Similarly, early caffeine/NSAID co-treatment resulted in effective decreases in pro-inflammatory cytokines (IL-1B, TNF-alpha, and IL-10) compared to late treatments (Figure; Panels A, C, E are Early; Panels B, D, F are Late).Conclusion(s): Our data show that neonatal IH is deleterious to lung and body growth. Early caffeine with or without ibuprofen is preferable, and confer synergistic effects for reducing IH-induced lung inflammation. The anti-inflammatory effects of caffeine may explain in part, its beneficial effects on the decreased risk for bronchopulmonary dysplasia.
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