A Prominent Role for Airway Epithelial NF-κB Activation in Lipopolysaccharide-Induced Airway Inflammation

Poynter, Matthew E.; Irvin, Charles G.; Janssen–Heininger, Yvonne M. W.

doi:10.4049/jimmunol.170.12.6257

Cited by 174 publications

(171 citation statements)

References 68 publications

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“…Previous studies manipulating the NF-B pathway using tissue-specific transgenes (20,22), bone marrow chimeras (17,48,49), and adenoviral vectors (19,21) suggest that NF-B activity in epithelial cells is involved in and/or necessary for initiating inflammatory responses elicited by Gram-negative stimuli. We conducted experiments using alveolar/bronchial epithelial-specific SPC-dnI B␣ transgenic mice to complement our findings in mice lacking RelA in all cells.…”

Section: Discussionmentioning

confidence: 99%

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Quinton

Jones

Simms

et al. 2007

The Journal of Immunology

127

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Eradication of bacteria in the lower respiratory tract depends on the coordinated expression of proinflammatory cytokines and consequent neutrophilic inflammation. To determine the roles of the NF-κB subunit RelA in facilitating these events, we infected RelA-deficient mice (generated on a TNFR1-deficient background) with Streptococcus pneumoniae. RelA deficiency decreased cytokine expression, alveolar neutrophil emigration, and lung bacterial killing. S. pneumoniae killing was also diminished in the lungs of mice expressing a dominant-negative form of IκBα in airway epithelial cells, implicating this cell type as an important locus of NF-κB activation during pneumonia. To study mechanisms of epithelial RelA activation, we stimulated a murine alveolar epithelial cell line (MLE-15) with bronchoalveolar lavage fluid (BALF) harvested from mice infected with S. pneumoniae. Pneumonic BALF, but not S. pneumoniae, induced degradation of IκBα and IκBβ and rapid nuclear accumulation of RelA. Moreover, BALF-induced RelA activity was completely abolished following combined but not individual neutralization of TNF and IL-1 signaling, suggesting either cytokine is sufficient and necessary for alveolar epithelial RelA activation during pneumonia. Our results demonstrate that RelA is essential for the host defense response to pneumococcus in the lungs and that RelA in airway epithelial cells is primarily activated by TNF and IL-1.

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Section: Discussionmentioning

confidence: 99%

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Quinton

Jones

Simms

et al. 2007

The Journal of Immunology

127

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“…These pathways all converge on the Rel/Nf-kB complex, which is translocated to the nucleus to regulate gene transcription. Recent studies have shown that bronchial epithelial cells express nuclear RelA in response to allergen or lipopolysaccharide-induced inflammation (Poynter et al, 2002(Poynter et al, , 2003(Poynter et al, , 2004. This is evidence that Nf-kB can act directly within airway epithelial cells but the downstream targets are not yet known.…”

Section: Discussionmentioning

confidence: 99%

Intercellular growth factor signaling and the development of mouse tracheal submucosal glands

Rawlins

Hogan

2005

Developmental Dynamics

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To provide a genetic framework for investigating changes in airway submucosal gland function in human respiratory disease, we have investigated their counterparts in normal and mutant mice. We describe their morphogenesis in relation to the expression of genes encoding conserved intercellular signaling pathways. Submucosal glands are severely reduced in number and size in mice heterozygous for Fgf10. Glands are completely absent in mice lacking Ectodysplasin (Eda) and Edaradd (Eda receptor adaptor protein), members of the tumor necrosis (TNF) superfamily of signaling factors. Furthermore, components of the Eda and closely related pathways are transcribed throughout the respiratory system in the adult mouse. Finally, the temporal and spatial pattern of Bmp4 expression suggests that it may control submucosal gland development and homeostasis. Taken together, our observations have important implications for the better understanding of the submucosal gland remodeling that occurs in human respiratory disease.

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“…This feedback mechanism might be a critical factor in explaining why lung epithelial cells eventually die in hyperoxia even though NF-κB activation was initiated by hyperoxia [16,45]. Together with its role in sensitizing the airway epithelium to oxidative apoptosis, the regulation of the steadystate levels of IκBα might be an important modulator of oxidative lung injury and pulmonary remodeling [70,77,[82][83][84][85].…”

Section: Redox Transcription Factors In Pulmonary Hyperoxic Cell Deathmentioning

confidence: 99%

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Zaher

Miller

Morrow

et al. 2007

Free Radical Biology and Medicine

121

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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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A Prominent Role for Airway Epithelial NF-κB Activation in Lipopolysaccharide-Induced Airway Inflammation

Cited by 174 publications

References 68 publications

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Intercellular growth factor signaling and the development of mouse tracheal submucosal glands

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

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