Investigation of the use of antioxidants to diminish the adverse effects of postnatal glucocorticoid treatment on mortality and cardiac development.
BACKGROUND
In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on growth and the cardiovascular system. Glucocorticoid excess promotes free radical overproduction and vascular dysfunction.


OBJECTIVE
We hypothesized that the adverse effects of postnatal glucocorticoid therapy are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects.


METHODS
Male rat pups received a clinically relevant course of dexamethasone (Dex), or Dex with vitamins C and E (DexCE), on postnatal days 1-6 (P1-6). Controls received saline (Ctrl) or saline with vitamins (CtrlCE).


RESULTS
At P21, Dex reduced survival (Ctrl: 96 vs. Dex: 70%) and promoted asymmetric growth restriction (ponderal index, Ctrl: 6.3 +/- 0.1 g . mm(-3) x 10(-5) vs. Dex: 7.4 +/- 0.2 g . mm(-3) x 10(-5)), both p < 0.05. Dex increased cardiac oxidative stress (protein expression: 4-HNE +20%, Hsp90 -42% and eNOS -54%), induced left ventricle (LV) wall thinning (LV wall volume: Ctrl: 47.2 +/- 1.2 mm(3) vs. Dex: 38.9 +/- 1.7 mm(3)) and decreased the ratio of the aortic lumen:total vessel area (Ctrl: 0.74 +/- 0.01 vs. Dex: 0.66 +/- 0.02), all p < 0.05. DexCE restored towards control values survival, growth symmetry the aortic lumen:total vessel area, and increased the cardiac expression of Hsp90 relative to Dex. In addition, relative to controls, the decrease in the cardiac expression of eNOS was no longer significant in DexCE animals (-20.3 +/- 14.4%, p > 0.05). However, DexCE did not prevent growth retardation, cardiac 4-HNE upregulation (DexCE: +29%) or LV thinning (DexCE: 40.1 +/- 1.1 mm(3)). Treatment of neonates with vitamins alone affected somatic growth and promoted thinner LV walls (CtrlCE: 39.9 +/- 0.5 mm(3), p < 0.05).


CONCLUSIONS
Combined glucocorticoid and antioxidant therapy in premature infants may be safer than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.
Adler
Alexandra
A
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Camm
Emily J
EJ
Hansell
Jeremy A
JA
Richter
Hans G
HG
Giussani
Dino A
DA
D000447:Aldehydes / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D002908:Chronic Disease; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D008171:Lung Diseases / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D014810:Vitamin E / Q000627:therapeutic use*
D000447:Aldehydes; D000975:Antioxidants; D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D014810:Vitamin E; D003907:Dexamethasone; D052250:Nitric Oxide Synthase Type III; C027576:4-hydroxy-2-nonenal; D001205:Ascorbic Acid