المؤلفون: Singh SP; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Chand HS; Lovelace Respiratory Research Institute, Albuquerque, NM 87108.; Florida International University, Miami, FL 33199., Langley RJ; Lovelace Respiratory Research Institute, Albuquerque, NM 87108.; University of Southern Alabama, Mobile, AL 36688., Mishra N; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Barrett T; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Rudolph K; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Tellez C; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Filipczak PT; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Belinsky S; Lovelace Respiratory Research Institute, Albuquerque, NM 87108., Saeed AI; Pulmonary and Critical Care Medicine, University of New Mexico Medical Center, Albuquerque, NM 87131., Sheybani A; Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, NM 87131; and., Exil V; Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, NM 87131; and., Agarwal H; Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, NM 87131; and., Sidhaye VK; Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205., Sussan T; Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205., Biswal S; Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205., Sopori M; Lovelace Respiratory Research Institute, Albuquerque, NM 87108; msopori@lrri.org.

المصدر: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 May 15; Vol. 198 (10), pp. 3815-3822. Date of Electronic Publication: 2017 Apr 05.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE

مواضيع طبية MeSH: Epigenesis, Genetic*, Asthma/*etiology , Asthma/*genetics , Bronchopulmonary Dysplasia/*etiology , Prenatal Exposure Delayed Effects/*immunology , Smoke/*adverse effects , Tobacco Smoke Pollution/*adverse effects, Alveolar Epithelial Cells/pathology ; Animals ; Apoptosis ; Asthma/immunology ; Asthma/physiopathology ; Bronchopulmonary Dysplasia/immunology ; Bronchopulmonary Dysplasia/physiopathology ; Core Binding Factor Alpha 3 Subunit/genetics ; Female ; Homeodomain Proteins/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Lung/pathology ; Mice ; MicroRNAs/genetics ; NF-kappa B p50 Subunit/genetics ; Nerve Growth Factors ; Neuropeptides/genetics ; Nicotine/adverse effects ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/physiopathology ; Smoking/adverse effects ; Th2 Cells/immunology

مستخلص: Embryonic development is highly sensitive to xenobiotic toxicity and in utero exposure to environmental toxins affects physiological responses of the progeny. In the United States, the prevalence of allergic asthma (AA) is inexplicably rising and in utero exposure to cigarette smoke increases the risk of AA and bronchopulmonary dysplasia (BPD) in children and animal models. We reported that gestational exposure to sidestream cigarette smoke (SS), or secondhand smoke, promoted nicotinic acetylcholine receptor-dependent exacerbation of AA and BPD in mice. Recently, perinatal nicotine injections in rats were reported to induce peroxisome proliferator-activated receptor γ-dependent transgenerational transmission of asthma. Herein, we show that first generation and second generation progeny from gestationally SS-exposed mice exhibit exacerbated AA and BPD that is not dependent on the decrease in peroxisome proliferator-activated receptor γ levels. Lungs from these mice show strong eosinophilic infiltration, excessive Th2 polarization, marked airway hyperresponsiveness, alveolar simplification, decreased lung compliance, and decreased lung angiogenesis. At the molecular level, these changes are associated with increased RUNX3 expression, alveolar cell apoptosis, and the antiangiogenic factor GAX, and decreased expression of HIF-1α and proangiogenic factors NF-κB and VEGFR2 in the 7-d first generation and second generation lungs. Moreover, the lungs from these mice exhibit lower levels of microRNA (miR)-130a and increased levels of miR-16 and miR-221. These miRs regulate HIF-1α-regulated apoptotic, angiogenic, and immune pathways. Thus the intergenerational effects of gestational SS involve epigenetic regulation of HIF-1α through specific miRs contributing to increased incidence of AA and BPD in the progenies.
(Copyright © 2017 by The American Association of Immunologists, Inc.)

المؤلفون: Kong X; Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA., Thimmulappa R, Kombairaju P, Biswal S

المصدر: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 Jul 01; Vol. 185 (1), pp. 569-77. Date of Electronic Publication: 2010 May 28.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE

مواضيع طبية MeSH: NADPH Oxidases/*physiology , NF-E2-Related Factor 2/*deficiency , NF-E2-Related Factor 2/*genetics , Reactive Oxygen Species/*metabolism , Sepsis/*immunology , Sepsis/*metabolism , Signal Transduction/*immunology , Toll-Like Receptor 4/*physiology, Animals ; Inflammation Mediators/physiology ; Lipopolysaccharides/antagonists & inhibitors ; Lipopolysaccharides/toxicity ; Lung/immunology ; Lung/pathology ; Macrophages, Alveolar/immunology ; Macrophages, Alveolar/metabolism ; Macrophages, Alveolar/pathology ; Macrophages, Peritoneal/immunology ; Macrophages, Peritoneal/metabolism ; Macrophages, Peritoneal/pathology ; Membrane Glycoproteins/deficiency ; Membrane Glycoproteins/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidase 2 ; NADPH Oxidases/antagonists & inhibitors ; NADPH Oxidases/deficiency ; NADPH Oxidases/genetics ; NF-E2-Related Factor 2/physiology ; Reactive Oxygen Species/antagonists & inhibitors ; Sepsis/mortality ; Toll-Like Receptor 4/metabolism

مستخلص: Sepsis syndrome is characterized by a dysregulated inflammatory response to infection. NADPH oxidase-dependent reactive oxygen species (ROS) play significant roles in the pathophysiology of sepsis. We previously showed that disruption of Nrf2, a master regulator of antioxidant defenses, caused a dysregulation of innate immune response that resulted in greater mortality in a polymicrobial sepsis and LPS shock model; however, the underlying mechanisms are unclear. In the current study, compared with wild-type (Nrf2(+/+)) macrophages, we observed greater protein kinase C-induced NADPH oxidase-dependent ROS generation in Nrf2-disrupted (Nrf2(-/-)) macrophages that was modulated by glutathione levels. To address the NADPH oxidase-mediated hyperinflammatory response and sepsis-induced lung injury and mortality in Nrf2(-/-) mice, we used double knockout mice lacking Nrf2 and NADPH oxidase subunit, gp91(phox) (Nrf2(-/-)//gp91(phox-/-)). Compared with Nrf2(+/+) macrophages, LPS induced greater activation of TLR4 as evident by TLR4 surface trafficking and downstream recruitment of MyD88 and Toll/IL-1R domain-containing adaptor in Nrf2(-/-) macrophages that was diminished by ablation of gp91(phox). Similarly, phosphorylation of IkappaB and IFN regulatory factor 3 as well as cytokine expression was markedly higher in Nrf2(-/-) macrophages; whereas, it was similar in Nrf2(+/+) and Nrf2(-/-)//gp91(phox-/-). In vivo studies showed greater LPS-induced pulmonary inflammation in Nrf2(-/-) mice that was significantly reduced by ablation of gp91(phox). Furthermore, LPS shock and polymicrobial sepsis induced early and greater mortality in Nrf2(-/-) mice; whereas, Nrf2(-/-)//gp91(phox-/-) showed prolonged survival. Together, these results demonstrate that Nrf2 is essential for the regulation of NADPH oxidase-dependent ROS-mediated TLR4 activation and lethal innate immune response in sepsis.

المؤلفون: Williams MA; Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. marc_williams@urmc.rochester.edu, Rangasamy T, Bauer SM, Killedar S, Karp M, Kensler TW, Yamamoto M, Breysse P, Biswal S, Georas SN

المصدر: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2008 Oct 01; Vol. 181 (7), pp. 4545-59.

نوع المنشور: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE

مواضيع طبية MeSH: Cell Differentiation/*immunology , Dendritic Cells/*immunology , Lymphocyte Activation/*immunology , NF-E2-Related Factor 2/*deficiency , NF-E2-Related Factor 2/*genetics , Oxidative Stress/*immunology , Particulate Matter/*toxicity , Th2 Cells/*immunology, Animals ; Baltimore ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/immunology ; Bone Marrow Cells/metabolism ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cells, Cultured ; Coculture Techniques ; Dendritic Cells/drug effects ; Dendritic Cells/metabolism ; Lung/cytology ; Lung/drug effects ; Lung/immunology ; Lung/metabolism ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/genetics ; Male ; Mice ; Mice, Inbred ICR ; Mice, Knockout ; Mice, Transgenic ; NF-E2-Related Factor 2/biosynthesis ; Oxidative Stress/drug effects ; Th2 Cells/drug effects ; Th2 Cells/metabolism

مستخلص: Oxidative stress is important in dendritic cell (DC) activation. Environmental particulate matter (PM) directs pro-oxidant activities that may alter DC function. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates expression of antioxidant and detoxification genes. Oxidative stress and defective antioxidant responses may contribute to the exacerbations of asthma. We hypothesized that PM would impart differential responses by Nrf2 wild-type DCs as compared with Nrf2(-/-) DCs. We found that the deletion of Nrf2 affected important constitutive functions of both bone marrow-derived and highly purified myeloid lung DCs such as the secretion of inflammatory cytokines and their ability to take up exogenous Ag. Stimulation of Nrf2(-/-) DCs with PM augmented oxidative stress and cytokine production as compared with resting or Nrf2(+/+) DCs. This was associated with the enhanced induction of Nrf2-regulated antioxidant genes. In contrast to Nrf2(+/+) DCs, coincubation of Nrf2(-/-) DCs with PM and the antioxidant N-acetyl cysteine attenuated PM-induced up-regulation of CD80 and CD86. Our studies indicate a previously underappreciated role of Nrf2 in innate immunity and suggest that deficiency in Nrf2-dependent pathways may be involved in susceptibility to the adverse health effects of air pollution in part by promoting Th2 cytokine responses in the absence of functional Nrf2. Moreover, our studies have uncovered a hierarchal response to oxidative stress in terms of costimulatory molecule expression and cytokine secretion in DCs and suggest an important role of heightened oxidative stress in proallergic Th2-mediated immune responses orchestrated by DCs.