Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers susceptibility to hyperoxic lung injury in mice

2003 ◽  
Vol 285 (1) ◽  
pp. L250-L257 ◽  
Author(s):  
Danielle Morse ◽  
Leo E. Otterbein ◽  
Simon Watkins ◽  
Sean Alber ◽  
Zhihong Zhou ◽  
...  
Keyword(s):  
Leukocyte Count ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Myeloperoxidase Activity ◽  
Adaptive Responses ◽  
Wild Type ◽  
Epithelial Cell Apoptosis ◽  
Hyperoxic Lung Injury ◽  
65 H

Hyperoxia generates an oxidative stress in the mouse lung, which activates the major stress-inducible kinase pathways, including c-Jun NH2-terminal kinase (JNK). We examined the effect of Jnk1 gene deletion on in vivo responses to hyperoxia in mice. The survival of Jnk1-/- mice was reduced relative to wild-type mice after exposure to continuous hyperoxia. Jnk1- /- mice displayed higher protein concentration in bronchoalveolar lavage (BAL) fluid and increased expression of heme oxygenase-1, a stress-inducible gene, after 65 h of hyperoxia. Contrary to other markers of injury, the leukocyte count in BAL fluid of Jnk1- /- mice was markedly diminished relative to that of wild-type mice. The decrease in BAL leukocyte count was not associated with any decrease in lung myeloperoxidase activity at baseline or after hyperoxia treatment. Pretreatment with inhaled lipopolysaccharide increased BAL neutrophil content and extended hyperoxia survival time to a similar extent in Jnk1- /- and wild-type mice. Associated with increased mortality, Jnk1- /- mice had increased pulmonary epithelial cell apoptosis after exposure to hyperoxia compared with wild-type mice. These results indicate that JNK pathways participate in adaptive responses to hyperoxia in mice.

scholarly journals Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury

1999 ◽  
Vol 277 (6) ◽  
pp. L1214-L1223 ◽  
Author(s):  
Funmei Yang ◽  
Jacqueline J. Coalson ◽  
Heather H. Bobb ◽  
Jacqueline D. Carter ◽  
Jameela Banu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Lung Damage ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Chronic Pulmonary Diseases ◽  
Hyperoxic Lung Injury ◽  
Key Participants

Oxidative stress plays a central role in the pathogenesis of acute and chronic pulmonary diseases. Safe sequestration of iron, which participates in the formation of the hydroxyl radical, is crucial in the lung's defense. We used a mouse line defective in the major iron transport protein transferrin to investigate the effect of aberrant iron metabolism on the lung's defense against oxidative injury. The tolerance to hyperoxic lung injury was greater in the hypotransferrinemic than in wild-type mice as documented by histopathology and biochemical indexes for lung damage. There was no increase in the levels of intracellular antioxidants, inflammatory cytokines, and heme oxygenase-1 in the hypotransferrinemic mouse lung compared with those in wild-type mice. However, there were elevated expressions of ferritin and lactoferrin in the lung of hypotransferrinemic mice, especially in the alveolar macrophages. Our results suggest that pulmonary lactoferrin and ferritin protect animals against oxidative stress, most likely via their capacity to sequester iron, and that alveolar macrophages are the key participants in iron detoxification in the lower respiratory tract.

scholarly journals A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

2009 ◽  
Vol 297 (4) ◽  
pp. L687-L697 ◽  
Author(s):  
Marwan Dib ◽  
Zsuzsanna Zsengeller ◽  
Alex Mitsialis ◽  
Bao Lu ◽  
Stewart Craig ◽  
...  
Keyword(s):  
Substance P ◽  
Lung Injury ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Tunel Staining ◽  
Wild Type ◽  
Bioactive Constituents ◽  
Targeted Deletion ◽  
Hyperoxic Lung Injury

The neuropeptide substance P manifests its biological functions through ligation of a G protein-coupled receptor, the NK1R. Mice with targeted deletion of this receptor reveal a preponderance of proinflammatory properties resulting from ligand activation, demonstrating a neurogenic component to multiple forms of inflammation and injury. We hypothesized that NK1R deficiency would afford a similar protection from inflammation associated with hyperoxia. Counter to our expectations, however, NK1R−/− animals suffered significantly worse lung injury compared with wild-type mice following exposure to 90% oxygen. Median survival was shortened to 84 h for NK1R−/− mice from 120 h for wild-type animals. Infiltration of inflammatory cells into the lungs was significantly increased; NK1R−/− animals also exhibited increased pulmonary edema, hemorrhage, and bronchoalveolar lavage fluid protein levels. TdT-mediated dUTP nick end labeling (TUNEL) staining was significantly elevated in NK1R−/− animals following hyperoxia. Furthermore, induction of metallothionein and Na+-K+-ATPase was accelerated in NK1R−/− compared with wild-type mice, consistent with increased oxidative injury and edema. In cultured mouse lung epithelial cells in 95% O2, however, addition of substance P promoted cell death, suggesting the neurogenic component of hyperoxic lung injury is mediated by additional mechanisms in vivo. Release of bioactive constituents including substance P from sensory neurons results from activation of the vanilloid receptor, TRPV1. In mice with targeted deletion of the TRPV1 gene, acute hyperoxic injury is attenuated relative to NK1R−/− animals. Our findings thus reveal a major neurogenic mechanism in acute hyperoxic lung injury and demonstrate concerted actions of sensory neurotransmitters revealing significant protection for NK1R-mediated functions.

Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury.

1996 ◽  
Vol 14 (6) ◽  
pp. 556-568 ◽  
Author(s):  
P J Lee ◽  
J Alam ◽  
S L Sylvester ◽  
N Inamdar ◽  
L Otterbein ◽  
...  
Keyword(s):  
Lung Injury ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Hyperoxic Lung Injury

scholarly journals TNF Is Necessary for Castration-Induced Prostate Regression, Whereas TRAIL and FasL Are Dispensable

2011 ◽  
Vol 25 (4) ◽  
pp. 611-620 ◽  
Author(s):  
Jennifer S. Davis ◽  
Kent L. Nastiuk ◽  
John J. Krolewski
Keyword(s):  
Mrna Levels ◽  
Wild Type ◽  
Mouse Prostate ◽  
Epithelial Cell Apoptosis ◽  
Androgen Withdrawal ◽  
Fas Signaling ◽  
Induced Apoptosis ◽  
Physiologic Role

TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal. Employing high-resolution serial magnetic resonance imaging to measure mouse prostate volume changes over time, we demonstrate that the extent of castration-induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes but not mice deficient for TNF-related apoptosis-inducing ligand or Fas signaling. Wild-type mice receiving soluble TNF (sTNF) receptor 2 (to bind TNF and block signaling) before castration exhibit an identical reduction of prostate regression. Together, these data indicate that uniquely among known extrinsic death signals, TNF is required for castration-induced prostate regression. Additionally, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate after castration. This is consistent with a paracrine role for TNF in prostate regression. When injected into the peritoneum of Tnf−/− mice at the time of castration, sTNF restores normal levels of prostate regression. However, wild-type mice receiving sTNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient but acts in the context of additional castration-induced signals. These findings support a physiologic role for TNF in prostate regression after androgen withdrawal. Understanding this role may lead to novel therapies for prostate cancer.

scholarly journals Regulation of Mycobacterium tuberculosis whiB3 in the Mouse Lung and Macrophages

2006 ◽  
Vol 74 (11) ◽  
pp. 6449-6457 ◽  
Author(s):  
N. Banaiee ◽  
W. R. Jacobs ◽  
J. D. Ernst
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Lung ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Environmental Signals ◽  
Immunodeficient Mice ◽  
Reverse Transcription Pcr ◽  
Factor Alpha

ABSTRACT Mycobacterium tuberculosis is a highly successful human pathogen, with ∼2 × 109 individuals infected globally. To understand the responses of M. tuberculosis to the in vivo environment, we studied the in vivo regulation of M. tuberculosis genes whose M. marinum homologs are induced in chronically infected frog tissues. The expression of 16S rRNA was shown to remain constant in M. tuberculosis under in vivo and in vitro conditions and therefore could be used for internal normalization in quantitative reverse transcription-PCR assays. We found whiB3, a putative transcriptional regulator implicated in mediating tissue damage, to be maximally induced at 2 weeks postinfection in the lungs of wild-type and immunodeficient (gamma interferon receptor−/−, Rag1−/−, and tumor necrosis factor alpha−/−) mice. At later time points in wild-type mice, whiB3 induction was decreased and gradually declined over the course of infection. In immunodeficient mice, whiB3 induction declined rapidly and was completely abolished in moribund animals. whiB3 was also found to be induced in naïve bone marrow-derived macrophages after 6 h of infection. whiB3 expression in vivo and in vitro was found to be inversely correlated with bacterial density. These results indicate that M. tuberculosis regulates the expression of whiB3 in response to environmental signals present in vivo and are consistent with a model of regulation by quorum sensing.

scholarly journals Tyrosine Mutation in AAV9 Capsid Improves Gene Transfer to the Mouse Lung

2016 ◽  
Vol 39 (2) ◽  
pp. 544-553 ◽  
Author(s):  
Sabrina V. Martini ◽  
Adriana L. Silva ◽  
Debora Ferreira ◽  
Rafael Rabelo ◽  
Felipe M. Ornellas ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Point Mutations ◽  
Lung Mechanics ◽  
Mouse Lung ◽  
Control Group ◽  
Polymorphonuclear Cells ◽  
Wild Type ◽  
Tyrosine Residues

Background/Aims: Adeno-associated virus (AAV) vectors are being increasingly used as the vector of choice for in vivo gene delivery and gene therapy for many pulmonary diseases. Recently, it was shown that phosphorylation of surface-exposed tyrosine residues from AAV capsid targets the viral particles for ubiquitination and proteasome-mediated degradation, and mutations of these tyrosine residues lead to highly efficient vector transduction in vitro and in vivo in different organs. In this study, we evaluated the pulmonary transgene expression efficacy of AAV9 vectors containing point mutations in surface-exposed capsid tyrosine residues. Methods: Eighteen C57BL/6 mice were randomly assigned into three groups: (1) a control group (CTRL) animals underwent intratracheal (i.t.) instillation of saline, (2) the wild-type AAV9 group (WT-AAV9, 1010 vg), and (3) the tyrosine-mutant Y731F AAV9 group (M-AAV9, 1010 vg), which received (i.t.) self-complementary AAV9 vectors containing the DNA sequence of enhanced green fluorescence protein (eGFP). Four weeks after instillation, lung mechanics, morphometry, tissue cellularity, gene expression, inflammatory cytokines, and growth factor expression were analyzed. Results: No significant differences were observed in lung mechanics and morphometry among the experimental groups. However, the number of polymorphonuclear cells was higher in the WT-AAV9 group than in the CTRL and M-AAV9 groups, suggesting that the administration of tyrosine-mutant AAV9 vectors was better tolerated. Tyrosine-mutant AAV9 vectors significantly improved transgene delivery to the lung (30%) compared with their wild-type counterparts, without eliciting an inflammatory response. Conclusion: Our results provide the impetus for further studies to exploit the use of AAV9 vectors as a tool for pulmonary gene therapy.

scholarly journals Heme Catabolism by Heme Oxygenase-1 Confers Host Resistance to Mycobacterium Infection

2013 ◽  
Vol 81 (7) ◽  
pp. 2536-2545 ◽  
Author(s):  
Sandro Silva-Gomes ◽  
Rui Appelberg ◽  
Rasmus Larsen ◽  
Miguel Parreira Soares ◽  
Maria Salomé Gomes
Keyword(s):  
Host Resistance ◽  
Mycobacterial Infection ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Content Type ◽  
Host Protection ◽  
Aerosol Infection ◽  
Systemic Infections

ABSTRACTHeme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by theHmox1gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (Mϕ) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1−/−) mice are more susceptible to intravenousMycobacterium aviuminfection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1+/+) controls. Furthermore,Hmox1−/−mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection withMycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed inM. avium-infectedHmox1−/−versusHmox1+/+SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected Mϕ, an effect mimicked by exogenous heme administration toM. avium-infected wild-type Mϕin vitroor to micein vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in Mϕ, contributing critically to host resistance toMycobacteriuminfection.

scholarly journals Interleukin-4 Enhances Pulmonary Clearance ofPseudomonas aeruginosa

1998 ◽  
Vol 66 (9) ◽  
pp. 4229-4236 ◽  
Author(s):  
Shilpa Jain-Vora ◽  
Ann Marie LeVine ◽  
Zissis Chroneos ◽  
Gary F. Ross ◽  
William M. Hull ◽  
...  
Keyword(s):  
Lavage Fluid ◽  
Secretory Protein ◽  
Clara Cell ◽  
Interleukin 4 ◽  
Mouse Lung ◽  
Bacterial Clearance ◽  
Wild Type ◽  
Rapid Reduction ◽  
Pulmonary Clearance

ABSTRACT To determine the effects of interleukin-4 (IL-4) on bacterial clearance from the mouse lung, transgenic mice expressing IL-4 in respiratory epithelial cells under the control of the Clara cell secretory protein promoter (CCSP-IL-4 mice) were infected intratracheally with Pseudomonas aeruginosa. Survival of CCSP-IL-4 mice following bacterial administration was markedly improved compared with that of control mice. While bacteria proliferated in lungs of wild-type mice, a rapid reduction in the number of bacteria was observed in the IL-4 mice as early as 6 h postinfection. Similarly, intranasal administration of IL-4 enhanced bacterial clearance from the lungs of wild-type mice. While acute and chronic IL-4 increased the numbers of neutrophils in bronchoalveolar lavage fluid, bacterial infection was associated with acute neutrophilic pulmonary infiltration, and this response was similar in the presence or absence of IL-4. Local administration or expression of IL-4 in the mouse lung enhanced pulmonary clearance of P. aeruginosa in vivo and decreased mortality following infection.

scholarly journals Parenteral iron formulations differentially affect MCP-1, HO-1, and NGAL gene expression and renal responses to injury

2010 ◽  
Vol 299 (2) ◽  
pp. F426-F435 ◽  
Author(s):  
Ali CM Johnson ◽  
Kirsten Becker ◽  
Richard A. Zager
Keyword(s):  
Renal Disease ◽  
Proximal Tubule ◽  
Cell Injury ◽  
Fe Deficiency ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Adaptive Responses ◽  
Mrna Induction ◽  
Parenteral Iron

Despite their prooxidant effects, ferric iron compounds are routinely administered to patients with renal disease to correct Fe deficiency. This study assessed relative degrees to which three clinically employed Fe formulations [Fe sucrose (FeS); Fe gluconate (FeG); ferumoxytol (FMX)] impact renal redox- sensitive signaling, cytotoxicity, and responses to superimposed stress [endotoxin; glycerol-induced acute renal failure (ARF)]. Cultured human proximal tubule (HK-2) cells, isolated proximal tubule segments (PTS), or mice were exposed to variable, but equal, amounts of FeS, FeG, or FMX. Oxidant-stimulated signaling was assessed by heme oxygenase-1 (HO-1) or monocyte chemoattractant protein (MCP)-1 mRNA induction. Cell injury was gauged by MTT assay (HK-2 cells), %LDH release (PTS), or renal cortical neutrophil gelatinase-associated lipoprotein (NGAL) protein/mRNA levels. Endotoxin sensitivity and ARF severity were assessed by TNF-α and blood urea nitrogen concentrations, respectively. FeS and FeG induced lethal cell injury (in HK-2 cells, PTS), increased HO-1 and MCP-1 mRNAs (HK-2 cells; in vivo), and markedly raised plasma (∼10 times), and renal cortical (∼3 times) NGAL protein levels. Both renal and extrarenal (e.g., hepatic) NGAL production likely contributed to these results, based on assessments of tissue and HK-2 cell NGAL mRNA. FeS pretreatment exacerbated endotoxemia. However, it conferred marked protection against the glycerol model of ARF (halving azotemia). FMX appeared to be “bioneutral,” as it exerted none of the above noted FeS/FeG effects. We conclude that 1) parenteral iron formulations that stimulate redox signaling can evoke cyto/nephrotoxicity; 2) secondary adaptive responses to this injury (e.g., HO-1/NGAL induction) can initiate a renal tubular cytoresistant state; this suggests a potential new clinical application for intravenous Fe therapy; and 3) FMX is bioneutral regarding these responses. The clinical implication(s) of the latter, vis a vis the treatment of Fe deficiency in renal disease patients, remains to be defined.

scholarly journals MiR-196a regulates heme oxygenase-1 by silencing Bach1 in the neonatal mouse lung

2016 ◽  
Vol 311 (2) ◽  
pp. L400-L411 ◽  
Author(s):  
Hayato Go ◽  
Ping La ◽  
Fumihiko Namba ◽  
Masato Ito ◽  
Guang Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heme Oxygenase ◽  
Mirna Expression ◽  
Developmental Differences ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Developmentally Regulated ◽  
Neonatal Mice ◽  
Hyperoxic Exposure

In the lung, heme oxygenase-1 (HO-1) is developmentally regulated, with its highest expression in the first days of life. In addition, neonatal mice have limited HO-1 induction in hyperoxia compared with adults. However, few reports have addressed the functional effect of microRNAs (miRNAs) in the regulation of HO-1 in vivo. The aims of the present study were to characterize changes in lung miRNA expression during postnatal development and in response to hyperoxic exposure, and to identify miRNAs that target lung HO-1 gene expression. Neonatal (<12 h old) and adult (2 mo old) mice were exposed to room air or hyperoxia (95% oxygen) for 72 h. TaqMan low-density array rodent miRNA assays were used to calculate miRNA expression changes between control and hyperoxia groups in neonatal and adult lungs. In neonates, we identified miR-196a, which binds to the 3′-untranslated region of the transcriptional repressor BTB and CNC homology 1 (Bach1) and regulates its expression, and subsequently leads to higher levels of lung HO-1 mRNA compared with levels in adults. Despite the increase at baseline, miR-196a was degraded in hyperoxia resulting in limited HO-1 induction in neonatal mice lungs. Furthermore, the developmental differences in lung HO-1 gene expression can be explained in part by the variation in miRNA-196a and its effect on Bach1. This report is the first to show developmental differences in lung miR-196a and its effect on Bach1 and HO-1 expression at baseline and in hyperoxia.

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