Sex differences in the expression of lung inflammatory mediators in response to ozone.
Sex differences in the incidence of respiratory diseases have been reported. Women are more susceptible to inflammatory lung disease induced by air pollution and show worse adverse pulmonary health outcomes than men. However, the mechanisms underlying these differences remain unknown. In the present study, we hypothesized that sex differences in the expression of lung inflammatory mediators affect sex-specific immune responses to environmental toxicants. We focused on the effects of ground-level ozone, a major air pollutant, in the expression and regulation of lung immunity genes. We exposed adult male and female mice to 2 ppm of ozone or filtered air (control) for 3 h. We compared mRNA levels of 84 inflammatory genes in lungs harvested 4 h postexposure using a PCR array. We also evaluated changes in lung histology and bronchoalveolar lavage fluid cell counts and protein content at 24 and 72 h postexposure. Our results revealed sex differences in lung inflammation triggered by ozone exposure and in the expression of genes involved in acute phase and inflammatory responses. Major sex differences were found in the expression of neutrophil-attracting chemokines (Ccl20, Cxcl5, and Cxcl2), the proinflammatory cytokine interleukin-6, and oxidative stress-related enzymes (Ptgs2, Nos2). In addition, the phosphorylation of STAT3, known to mediate IL-6-related immune responses, was significantly higher in ozone-exposed mice. Together, our observations suggest that a differential regulation of the lung immune response could be implicated in the observed increased susceptibility to adverse health effects from ozone observed in women vs. men.
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Noe
N
Cabello
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Vikas
V
Mishra
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Utkarshna
U
Sinha
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Susan L
SL
DiAngelo
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Zissis C
ZC
Chroneos
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Ndifreke A
NA
Ekpa
Department of Comparative Medicine, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Timothy K
TK
Cooper
Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
Carla R
CR
Caruso
Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Humanities, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania pzs13@psu.edu.
Patricia
http://orcid.org/0000-0001-7083-8915
P
Silveyra
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002199:Capillary Permeability; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D018384:Oxidative Stress; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
D000393:Air Pollutants; D018836:Inflammation Mediators; D007378:Interleukins; D051192:Receptors, Pattern Recognition; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D010126:Ozone
STAT3; inflammation; lung disease; macrophage inflammatory proteins; oxidative stress