NF-κB and STAT3 signaling hubs for lung innate immunity

Quinton, Lee J.; Mizgerd, Joseph P.

doi:10.1007/s00441-010-1044-y

Cited by 60 publications

(59 citation statements)

References 138 publications

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“…Animal experiments demonstrate that interruptions in NF-kB signaling, including mutations of NF-kB RelA (16), intracellular signaling pathways that stimulate NF-kB (17), or receptor complexes activating these pathways (18), can compromise host defenses and predispose to lung infection. Conversely, animal models in which NF-kB activity is exaggerated reveal that this transcriptional activity is sufficient to induce or exacerbate lung injury (14,15). Similar observations have been collected from human patients.…”

Section: Inflammation and Innate Immunity During Lung Infectionsupporting

confidence: 53%

“…The transcription factor nuclear factor (NF)-kB operates as a molecular fulcrum balancing the initial innate immune response to microbes in the lungs (14,15). Animal experiments demonstrate that interruptions in NF-kB signaling, including mutations of NF-kB RelA (16), intracellular signaling pathways that stimulate NF-kB (17), or receptor complexes activating these pathways (18), can compromise host defenses and predispose to lung infection.…”

Section: Inflammation and Innate Immunity During Lung Infectionmentioning

confidence: 99%

“…Inflammatory lung injury can cause the death and replacement of structural cells, and molecular and cellular pathways involved in protecting from cytotoxicity and enhancing the proliferation, migration, and differentiation of replacement cells are emerging as exciting areas related to pulmonary immunity and infection. Just as NF-kB is a signaling hub central to innate immunity, STAT3 may be a central mediator of cytoprotection (15). STAT3 induces gene expression programs that prevent cell death, promote cell migration, and enhance cell proliferation, all of which may contribute to lung protection.…”

Section: Repair Resolution and Regeneration After Lung Injurymentioning

confidence: 99%

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Respiratory Infection and the Impact of Pulmonary Immunity on Lung Health and Disease

Mizgerd

2012

Am J Respir Crit Care Med

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Acute lower respiratory tract infection is responsible for an inordinate disease burden. Pulmonary immunity determines the outcomes of these infections. The innate and adaptive immune responses to microbes in the lung are critical to maintaining a healthy respiratory system and preventing pulmonary disease. In addition to balancing antimicrobial defense against the risk of lung injury during the immediate infection, the shaping of pulmonary immunity by respiratory infection contributes to the pathophysiology of many and even perhaps most chronic pulmonary diseases. This Pulmonary Perspective aims to communicate two interconnected points. First, tremendous morbidity and mortality result from inadequate, misguided, or excessive pulmonary immunity. Second, our understanding of pulmonary immunity is at an exciting stage of rapid developments and discoveries, but many questions remain. Further advances in pulmonary immunity and elucidation of the cellular and molecular responses to microbes in the lung are needed to develop novel approaches to predicting, preventing, and curing respiratory disease.

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Section: Inflammation and Innate Immunity During Lung Infectionsupporting

confidence: 53%

Section: Inflammation and Innate Immunity During Lung Infectionmentioning

confidence: 99%

Section: Repair Resolution and Regeneration After Lung Injurymentioning

confidence: 99%

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Respiratory Infection and the Impact of Pulmonary Immunity on Lung Health and Disease

Mizgerd

2012

Am J Respir Crit Care Med

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“…NF-kB is a transcription factor that can respond quickly to proinflammatory signals or injurious stimuli, and its activation through post-translational modifications (eg, phosphorylation of serine 536) 45 leads to induction of several genes important in host defense. 24,46 Although NF-kB activation is initially host protective, promoting host resistance to pathogens, many of the genes it up-regulates have proinflammatory activity, and failure to counterregulate NF-kB signaling in a timely manner can lead to tissue damage. 46 Herein, AT-RvD3 directly limited A549 epithelial cell activation of an NF-kB reporter in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Lung injury elicits NF-kB activation as a key regulator of tissue inflammation, 24 so we next explored the influence of AT-RvD3 on NF-kB expression and activation. First, in vitro, we used a lung epithelial cell line stably transfected with a fluorescent NF-kB reporter (described in Materials and Methods).…”

Section: Rvd3 and At-rvd3 Limit Activation Of The Nf-kb Pathwaymentioning

confidence: 99%

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

Colby

Abdulnour

Sham

et al. 2016

The American Journal of Pathology

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Acute lung injury is a life-threatening condition caused by disruption of the alveolar-capillary barrier leading to edema, influx of inflammatory leukocytes, and impaired gas exchange. Specialized proresolving mediators biosynthesized from essential fatty acids, such as docosahexaenoic acid, have tissue protective effects in acute inflammation. Herein, we found that the docosahexaenoic acidederived mediator resolvin D3 (RvD3): 4S,11R,17S-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid was present in uninjured lungs, and increased significantly 24 to 72 hours after hydrochloric acideinitiated injury. Because of its delayed enzymatic degradation, we used aspirin-triggered (AT)-RvD3: 4S,11R,17R-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid, a 17R-epimer of RvD3, for in vivo experiments. Histopathological correlates of acid injury (alveolar wall thickening, edema, and leukocyte infiltration) were reduced in mice receiving AT-RvD3 1 hour after injury. AT-RvD3etreated mice had significantly reduced edema, as demonstrated by lower wet/dry weight ratios, increased epithelial sodium channel g expression, and more lymphatic vessel endothelial hyaluronan receptor 1-positive vascular endothelial growth factor receptor 3-positive lymphatic vessels. Evidence for counterregulation of NF-kB by RvD3 and AT-RvD3 was seen in vitro and by AT-RvD3 in vivo. Increases in lung epithelial cell proliferation and bronchoalveolar lavage fluid levels of keratinocyte growth factor were observed with AT-RvD3, which also promoted cutaneous re-epithelialization. Together, these data demonstrate protective actions of RvD3 and AT-RvD3 for injured mucosa that accelerated restoration of epithelial barrier and function. (Am J Pathol 2016 http://dx.doi.org/10.1016/j.ajpath.2016 Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious conditions characterized by loss of normal epithelial and endothelial barrier function, leading to pulmonary edema and infiltration of leukocytes culminating in significant impairments in gas exchange. 1 ARDS and its milder form, ALI, are serious conditions characterized by loss of normal epithelial and endothelial barrier function, leading to pulmonary edema and infiltration of leukocytes culminating in significant impairments in gas exchange. 1 ALI is a common condition, affecting approximately 200,000 patients a year in the United States alone. 2 Although our understanding of the pathophysiological changes associated with ALI/ARDS has improved since its original description, effective management of this condition still proves difficult, and mortality remains approximately 40%. 2 Aspiration pneumonia/pneumonitis is a common cause of ALI/ARDS characterized by direct damage to lung epithelia (because of the low pH of gastric contents) followed by extensive sloughing of the injured epithelial cells. 3 Despite significant damage to the epithelial barrier,

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Exposure to aerosolized staphylococcal enterotoxin B potentiated by lipopolysaccharide modifies lung transcriptomes and results in lung injury in the mouse model

Zong

Gan

Wang

et al. 2022

J of Applied Toxicology

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Lipopolysaccharide (LPS) is one of the main constituents of the cell wall in Gram-negative bacteria. Staphylococcal enterotoxin B (SEB) is produced by the Gram-positive opportunistic pathogen, Staphylococcus aureus. Emerging evidence suggests that intraperitoneal injection of LPS combined with low-dose aerosolized SEB exposure can cause severe lung injury and even death, while SEB or LPS alone cause neither mortality nor severe pulmonary symptoms in mice. However, pulmonary effects from exposure to aerosolized SEB potentiated by LPS have not been evaluated. This study investigates the global transcriptome profile of lung tissue in mice after exposure to aerosolized SEB potentiated by LPS or LPS alone. A mouse model of intratracheal exposure to LPS-potentiated aerosolized SEB is established and described through histological examination. Transcriptome analysis revealed LPS-potentiated aerosolized SEB affected mouse lungs within 72 h post-SEB inhalation, gradually causing lung injury starting from 24 h post inhalation. Hub genes leading to lung injury at 48 h post inhalation have been identified. Flow cytometry revealed that LPS potentiation of low-dose SEB produces a superantigen response that T cells expressing a particular T cell receptor Vβ induces a proliferation response by 72 h post inhalation in the lungs of mice. This study represents the first research to investigate pulmonary transcriptional responses of LPS-potentiated aerosolized low-dose SEB exposure. This research helps to elucidate the molecular mechanisms underlying the process by which the two bacterial components combined to produce lung damage and provides an insight into potential treatments for alleviating inflammation of the lung when coinfection is present.

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NF-κB and STAT3 signaling hubs for lung innate immunity

Cited by 60 publications

References 138 publications

Respiratory Infection and the Impact of Pulmonary Immunity on Lung Health and Disease

Respiratory Infection and the Impact of Pulmonary Immunity on Lung Health and Disease

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

Exposure to aerosolized staphylococcal enterotoxin B potentiated by lipopolysaccharide modifies lung transcriptomes and results in lung injury in the mouse model

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