TY - JOUR
T1 - Sex-specific differences in hyperoxic lung injury in mice
T2 - Implications for acute and chronic lung disease in humans
AU - Lingappan, Krithika
AU - Jiang, Weiwu
AU - Wang, Lihua
AU - Couroucli, Xanthi I.
AU - Barrios, Roberto
AU - Moorthy, Bhagavatula
N1 - Funding Information:
This work was in part supported by RO1 grants HL-087174 , ES-019689 , and HL-112516 to B.M., and HL-088343 to X.C. The study sponsors had no involvement in study design, data collection, analysis and interpretation, writing of the report or decision to submit the paper for publication. The authors thank Dr. Edward Felix of the M.D. Anderson Cancer Center in carrying out LC–MS/MS analyses for determination of 8-iso-PGF 2α levels. We thank Dr. Chandra Srinivasan for reading the manuscript critically and for his insightful comments.
PY - 2013/10/15
Y1 - 2013/10/15
N2 - Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72h of hyperoxia (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F>M) and VEGF (M>F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans.
AB - Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72h of hyperoxia (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F>M) and VEGF (M>F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans.
KW - Cytochrome P4501A1
KW - Hyperoxia
KW - Inflammation
KW - Lung injury
KW - Oxidative stress
KW - Sex-differences
UR - http://www.scopus.com/inward/record.url?scp=84883779103&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883779103&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2013.06.007
DO - 10.1016/j.taap.2013.06.007
M3 - Article
C2 - 23792423
AN - SCOPUS:84883779103
SN - 0041-008X
VL - 272
SP - 281
EP - 290
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 2
ER -