The Role of Nuclear Factor Kappa B in the Pathogenesis of Pulmonary Diseases: Implications for Therapy

Wright, Jeffrey G.; Christman, John W.

doi:10.1007/bf03256650

Cited by 166 publications

(104 citation statements)

References 61 publications

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“…7). NF-κB, an important mediator of immune and inflammatory responses, has been strongly implicated in ALI (46)(47)(48)(49)(50)(51). Evidence supports the notion that NF-κB induces transcription of human and rat D2 gene expression, and, indeed, a potent NF-κB-binding site has been demonstrated in the human D2 gene (52,53).…”

Section: Discussionmentioning

confidence: 74%

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Barca-Mayo

Liao

DiCosmo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) metabolism, mediated by deiodinase types 1, 2, and 3 (D1, D2, and D3) is profoundly affected by acute illness. We examined the role of TH metabolism during ventilator-induced lung injury (VILI) in mice. Mice exposed to VILI recapitulated the serum TH findings of acute illness, namely a decrease in 3,5,3′-triiodothyronine (T 3 ) and thyroid-stimulating hormone and an increase in reverse T 3 . Both D2 immunoreactivity and D2 enzymatic activity were increased significantly. D1 and D3 activity did not change. Using D2 knockout (D2KO) mice, we determined whether the increase in D2 was an adaptive response. Although similar changes in serum TH levels were observed in D2KO and WT mice, D2KO mice exhibited greater susceptibility to VILI than WT mice, as evidenced by poorer alveoli integrity and quantified by lung chemokine and cytokine mRNA induction. These data suggest that an increase in lung D2 is protective against VILI. Similar findings of increased inflammatory markers were found in hypothyroid WT mice exposed to VILI compared with euthyroid mice, indicating that the lungs were functionally hypothyroid. Treatment of D2KO mice with T 3 reversed many of the lung chemokine and cytokine profiles seen in response to VILI, demonstrating a role for T 3 in the treatment of lung injury. We conclude that TH metabolism in the lung is linked to the response to inflammatory injury and speculate that D2 exerts its protective effect by making more TH available to the injured lung tissue.nonthyroidal illness | euthyroid sick | reverse triiodothyronine | bronchial alveolar lavage | sepsis T hyroid hormone [TH, here denoting the active hormone 3,5,3′-triiodothyronine (T 3 ) and its precursor thyroxine (T 4 )] is necessary for the normal development and function of virtually every vertebrate tissue. Although the thyroid gland is predominantly responsible for the production and release of T 4 , the cellular bioavailability of the active T 3 depends on TH-specific transporters and tissue TH metabolism. Metabolism of TH is regulated by three iodothyronine deiodinases. Both type 1 (D1) and type 2 (D2) deiodinases serve to generate bioactive T 3 by outer-ring deiodination of T 4 . D2 has a major role in the intracellular generation of the active TH in mouse; the role of the D1, with its broad substrate specificity and ability to carry out both outer-and inner-ring deiodination, is less well understood. In contrast, type 3 iodothyronine deiodinase (D3) inactivates TH by inner-ring deiodination of T 4 to reverse T 3 (3′,5,3-triiodothyronine; rT 3 ) and T 3 to 3,3′-diiodothyronine (T 2 ), both biologically inactive compounds (1).Studies have elucidated the dynamic effects of TH action on brain, bone, liver (2-5), and maturation of the fetal lung (6, 7), but little is known regarding the role of TH in adult lung physiology. Until now, evidence suggesting that TH influences adult lung physiology has been indirect and based on the presence of TH receptors (8), deiodinases (9-12), and measured TH concentrations (10,13,14) i...

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Section: Discussionmentioning

confidence: 74%

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Barca-Mayo

Liao

DiCosmo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The transcription factor NF-kB, regulates the expression of a large number of inflammatory genes, is involved in the pathogenesis of ALI and is known as an important target for anti-inflammatory molecules (Wright & Christman, 2003). Under resting conditions, NF-kB is located in the cytoplasm bound to IkB.…”

Section: Discussionmentioning

confidence: 99%

Protective effects and mechanisms of mogroside V on LPS-induced acute lung injury in mice

Shi

Zheng

Wang

et al. 2014

Pharmaceutical Biology

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Protective effects and mechanisms of mogroside V on LPS-induced acute lung injury in mice, Pharmaceutical Biology, 52:6, 729-734, DOI: 10.3109/13880209.2013 Materials and methods:Female BALB/c mice were treated with commercial mogroside V (2.5, 5 and 10 mg/kg) for 1 h prior to intranasal injection of LPS (10 mg in 50 ml). After 12 h, airway inflammation in the ALI model was determined by the wet/dry weight (W/D) ratio, myeloperoxidase (MPO) activity of lung tissue, leukocyte recruitment and cytokine levels in the bronchoalveolar lavage fluid (BALF). Additionally, lung tissue was examined by histology and western blotting to investigate the changes in pathology and the signalling in the presence and absence of mogroside V. Results: Mogroside V at 5 and 10 mg/kg inhibited airway inflammation induced by LPS as measured by the decrease in the histological changes (44 and 67.3% reduction in lung injury score, respectively), a 28.9 and 55.3% reduction in lung MPO activity, and inflammatory cell counts, interleukin-1b (IL-1b, 382 and 280 pg/ml, respectively), IL-6 (378 and 232 pg/ml, respectively) and tumor necrosis factor-a (TNF-a, 12.5 and 7.8 ng/ml, respectively) levels in the BALF. Additionally, mogroside V treatment reduced the activation of cyclooxygenase 2 (COX-2), inducible NO synthase (iNOS), and the nuclear factor (NF)-kB. Discussions and conclusions: Together, these data suggest that mogroside V has the potential to protect against LPS-induced airway inflammation in a model of ALI.

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“…Neutrophil apoptosis, regulated by NFκB, plays a critical role in the resolution of inflammation associated with these disorders (28)(29)(30)(31)(32)49). Although studies have shown that NFκB is activated in patients with ALI, sepsis, and BPD (4,(30)(31)(32)(33)44), the stage of NFκB activation in these patients is not known. It seems plausible that it is the persistent NFκB activity, and not the early NFκB activation induced by neutrophil stimulation for 30 min, that is associated with the tissue injury in these inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Increased activation of NFκB in neutrophils has been associated with the pathogenesis of ALI, BPD, sepsis, and other inflammatory diseases (28)(29)(30)(31)(32)(33). Whereas the acute NFκB activation induced by neutrophil stimulation for 30-60 min has been well documented (34)(35)(36)(37)(38)(39)(40)(41), NFκB activation during the prolonged neutrophil stimulation that is likely to occur in inflammatory disorders has not been previously studied.…”

Section: Introductionmentioning

confidence: 99%