Lung Inflammation in Hyperoxia Can Be Prevented By Antichemokine Treatment in Newborn Rats

Deng, Hui; Mason, S. Nicholas; Auten, Richard L.

doi:10.1164/ajrccm.162.6.9911020

Cited by 103 publications

(89 citation statements)

References 34 publications

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“…The cellular distribution of the EGFR in the lung is broad, including fibroblasts and smooth muscle cells as well as epithelial cells. In addition, macrophages, mast cells and T cells also have been reported to express the EGFR [14,22] and could potentially be sources of IL-6, CINC-1 and eotaxin [23][24][25]. The EGFR blockade in these cells may contribute to the reductions of these chemokines/cytokines.…”

Section: Discussionmentioning

confidence: 99%

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Tsuchiya

Takeda

et al. 2010

Eur J Immunol

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EGF receptor (EGFR) is involved in cell differentiation and proliferation in airways and may trigger cytokine production by T cells. We hypothesized that EGFR inhibition at the time of allergic sensitization may affect subsequent immune reactions. Brown Norway rats were sensitized with OVA, received the EGFR tyrosine kinase inhibitor, AG1478 from days 0 to 7 and OVA challenge on day 14. OVA-specific IgE in serum and cytokines and chemokines in BAL were measured 24 h after challenge. To evaluate effects on airway hyperresponsiveness (AHR), rats were sensitized, treated with AG1478, intranasally challenged, and then AHR was assessed. Furthermore chemotactic activity of BALF for CD4 1 T cells was examined. The eosinophils, neutrophils and lymphocytes in BAL were increased by OVA and only the lymphocytes were reduced by AG1478. OVA significantly enhanced IL-6 concentration in BAL, which was inhibited by AG1478. However AHR, OVA-specific IgE and IL-4 mRNA expression in CD4 1 T cells were not affected by AG1478. BALF from OVAsensitized/challenged rats induced CD4 1 T-cell migration, which was inhibited by both AG1478 treatment in vivo and neutralization of IL-6 in vitro. EGFR activation during sensitization may affect the subsequent influx of CD4 1 T cells to airways, mainly mediated through IL-6.Key words: Asthma . CD4 1 T cells . EGF receptors . IL-6Supporting Information available online IntroductionThe EGF receptor (EGFR) is involved in the regulation of cell differentiation and proliferation and in the pathogenesis of various diseases including epithelial tumors [1,2]. The importance of the EGFR axis in cancer has best been studied in breast malignancies. However, the EGFR signaling pathway is implicated in airway biology and EGFR is expressed by many cell types in the lung, including smooth muscle cells, endothelium, fibroblasts and epithelium [3,4]. Human asthmatic airways show increased EGFR immunoreactivity in airway epithelium, glands, and smooth muscle [5] and EGFR activation has been reported to promote epithelial repair and to induce mucin production and remodeling of airway tissues [6,7]. We previously reported that multiple OVA challenges increased protein expression of the EGFR ligand, heparin-binding EGF-like 1590growth factor (HB-EGF) in airway epithelium in Brown Norway (BN) rats [4]. The inhibition of the tyrosine kinase signaling cascade might have therapeutic effects in asthma [8].Ligands for the EGFR found in the lung include EGF, TGF-a, amphiregulin, epiregulin and HB-EGF, all of which are synthesized as transmembrane precursors and are proteolytically cleaved by metalloproteases such as ADAM 10 and ADAM 17 [3]. Binding of these ligands to the receptor causes activation of the tyrosine kinase and receptor autophosphorylation. AG1478, a selective inhibitor of the EGFR tyrosine kinase (EGFR-TK), prevents ligand-induced EGFR phosphorylation and has antitumor activity [9]. AG1478 inhibits the proliferation of lung fibroblasts in vitro and has protective effects against bleomycin and vanadium pento...

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Section: Discussionmentioning

confidence: 99%

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Tsuchiya

Takeda

et al. 2010

Eur J Immunol

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“…Increased levels of IL-8 are detected in the lung during acute lung inflammation [116,117]. IL-8 produces its chemotactic activity through its interaction with both C-X-C chemokine receptor-1 and -2 (CXCR1 and CXCR2) [118,119].…”

Section: Proinflammatory Responses In Hyperoxic Lung Injurymentioning

confidence: 99%

“…Following exposure to 80% O 2 for 6 days, CXCR2 −/− mice showed reduced neutrophil sequestration, which is associated with significantly decreased lung vascular permeability, edema and injury [121]. Furthermore, administration of neutralizing antibodies and antagonists of CXCR2 ligand, such as cytokine-induced neutrophil chemoattractant-1 (CINC-1), reduced the neutrophil mediated inflammatory responses and markedly increased survival of adult mice subjected to hyperoxia [118,122,123]. Another CXCR2 antagonist, SB265610, blocked chemokine effects on neutrophil viability and lung apoptosis in new born rats exposed to 95% O 2 for 8 days [122].…”

Section: Proinflammatory Responses In Hyperoxic Lung Injurymentioning

confidence: 99%

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Zaher

Miller

Morrow

et al. 2007

Free Radical Biology and Medicine

123

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Mechanical ventilation with hyperoxia is necessary to treat critically ill patients. However, prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen species (ROS), which can cause acute inflammatory lung injury. One of the major effects of hyperoxia is the injury and death of pulmonary epithelium, which is accompanied by increased levels of pulmonary proinflammatory cytokines and excessive leukocyte infiltration. A thorough understanding of the signaling pathways leading to pulmonary epithelial cell injury/death may provide some insights into the pathogenesis of hyperoxia-induced acute inflammatory lung injury. This review focuses on epithelial responses to hyperoxia and some of the major factors regulating pathways to epithelial cell injury/death, and proinflammatory responses upon exposure to hyperoxia. We discuss in detail some of the most interesting players, such as, NF-κB, that can modulate both proinflammatory responses and cell injury/death of lung epithelial cells. A better appreciation for the functions of these factors will no doubt help us to delineate the pathways to hyperoxic cell death and proinflammatory responses.

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“…The cytokine, MIP‐2 produced by monocytes, macrophages, and dendritic cells, stimulate neutrophils to secrete inflammatory cytokines such as interleukin‐6 and interleukin‐1 (Deng et al. 2000; De Filippo et al. 2008).…”

Section: Discussionmentioning

confidence: 99%

Nfib hemizygous mice are protected from hyperoxic lung injury and death

et al. 2017

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Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild‐type (Wt) littermates were exposed to 100% O2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real‐time PCR. Unexpectedly, Nfib hemizygous mice (0/14–0%) had significantly lower mortality compared to Wt mice (10/22–45%) at 80 h of hyperoxia (P < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP‐2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild‐type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild‐type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development.

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Lung Inflammation in Hyperoxia Can Be Prevented By Antichemokine Treatment in Newborn Rats

Cited by 103 publications

References 34 publications

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Nfib hemizygous mice are protected from hyperoxic lung injury and death

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