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PMID: 22701723 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Antioxidant protects against increases in low molecular weight hyaluronan and inflammation in asphyxiated newborn pigs resuscitated with 100% oxygen.

PloS one ·Vol. 7 ·No. 6 ·2012-00-00 ·Pages e38839

Østerholt HC, Dannevig I, Wyckoff MH, Liao J, Akgul Y, Ramgopal M, Mija DS, Cheong N, Longoria C, Mahendroo M, Nakstad B, Saugstad OD, Savani RC

Abstract

Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3-nitrotyrosine (3-NT), LMW HA, inflammation, TNFα and IL1ß in a newborn pig model of resuscitation. Newborn pigs (n = 40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNFα and IL1ß were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNFα and IL1ß expression. Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNFα and IL1ß expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation.

MeSH Terms
Acetylcysteine/metabolism,pharmacology Analysis of Variance Animals Animals, Newborn Antioxidants/metabolism,pharmacology Asphyxia/physiopathology,therapy Bronchoalveolar Lavage DNA Primers/genetics Enzyme-Linked Immunosorbent Assay Hyaluronic Acid/metabolism Interleukin-1beta/metabolism Lung/metabolism Oxidative Stress/drug effects,physiology Oxygen Inhalation Therapy/adverse effects Peroxynitrous Acid/metabolism Real-Time Polymerase Chain Reaction Sus scrofa Tumor Necrosis Factor-alpha/metabolism Tyrosine/analogs & derivatives,metabolism
Chemicals
Antioxidants DNA Primers Interleukin-1beta Tumor Necrosis Factor-alpha Peroxynitrous Acid 3-nitrotyrosine Tyrosine Hyaluronic Acid Acetylcysteine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Østerholt Helene C D
Department of Pediatrics, Akershus University Hospital, Lørenskog, Norway.
Dannevig Ingrid
Wyckoff Myra H
Liao Jie
Akgul Yucel
Ramgopal Mrithyunjay
Mija Dan S
Cheong Naeun
Longoria Christopher
Mahendroo Mala
Nakstad Britt
Saugstad Ola D
Savani Rashmin C
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0038839
Published
2012-00-00
Epub
2012-00-11
Pages
e38839
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3372475
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0038839 PMC Full Text View journal details
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