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"Kirkham, Paul"
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LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling
COPD is a disease of innate immunity and bacterial infections are a dominant cause of exacerbations in the later stages resulting in poor health and high mortality. The pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) is sensed by immune cells through activation of the toll-like receptor 4 (TLR4). This leads to the activation of NADPH oxidase (NOX) and NF-κB which together drive COPD inflammation. In this study we show in human PBMCs that LPS stimulated proinflammatory cytokine release (CXCL8 and IL6) was inhibited by approximately 50% by the broad specificity phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Our results also demonstrate that activation of PI3K following LPS stimulation is mediated by a NOX4 dependent mechanism releasing endogenous H
2
O
2
, as the NOX4 inhibitor apocynin blocked LPS induced AKT phosphorylation. Moreover, LPS-induced PI3K activation was inhibited by the anti-oxidant N-acetylcysteine in a concentration dependent manner (IC
50
~100 μM). In addition, our data demonstrated that inhibition of small G proteins, by pre-treatment with pertussis toxin, inhibited LPS-induced AKT phosphorylation. Furthermore, the G-protein inhibitors pertussis toxin and mastoparan both inhibited LPS-induced CXCL8 and IL-6 release by approximately 50%. Together, these data indicate there is a mechanism in human PBMCs where TLR4 activation by LPS leads to ROS generation through NOX4 and activation of the PI3K pathway. This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines.
Journal Article
Superman Action Comics Rebirth deluxe edition
\"Superman returns to Metropolis just in time to meet the city of tomorrow's newest protector: Lex Luthor. But it's not long before these dueling titans meet someone unexpected -- the new Clark Kent! The two arch-enemies must put aside their differences and face the common threat of Doomsday, as Jimmy Olsen and the Planet staff try to uncover the truth: who is the man claiming to be Clark Kent?\"-- Provided by publisher.
Book
The potential role of 1,25(OH)2D3 (Active vitamin D3) in modulating macrophage function; implications for chronic obstructive pulmonary disease (COPD)
Macrophages play an important role in tissue homeostasis, inflammation, and repair, displaying remarkable plasticity by polarising towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes. In chronic obstructive pulmonary disease (COPD), this regulatory balance is disrupted, resulting in sustained tissue damage and impaired repair capability. Defective efferocytosis and dysregulated macrophage phenotypes are key contributors to COPD pathogenesis. Emerging evidence suggests that vitamin D3, particularly its active form 1,25(OH)
2
D
3
, has an immunomodulatory effect on reprogramming macrophages towards an M2 phenotype. This review examines the molecular mechanisms through which 1,25(OH)
2
D
3
is reported to influence macrophage metabolism, surface marker expression, and intracellular signalling. Overall, the review suggests that 1,25(OH)
2
D
3
-mediated reprogramming of macrophage phenotype and function offers a potential therapeutic approach to mitigate persistent inflammation and tissue destruction in COPD. Moreover, future research should focus on exploring the detailed molecular pathway of 1,25(OH)
2
D
3
action in COPD macrophages and validating its clinical effects as part of personalised treatment strategies.
Evidence suggests that 1,25(OH)
2
D
3
enhances mitochondrial function and shift macrophage metabolism from glycolysis to oxidative phosphorylation through metabolic reprogramming facilitating M1-to-M2 polarisation. 1,25(OH)
2
D
3
also modulates macrophage phenotype by regulating M2-associated surface markers (CD36, CD163, CD206, TIM-3) and downregulating pro-inflammatory mediators (CD86, iNOS, HLA-DR). It promotes the secretion of anti-inflammatory cytokines IL-10 and TGF-β while suppressing IL-1β, IL-6 and TNF production. Mechanistically, 1,25(OH)
2
D
3
regulates macrophage polarisation through multiple signalling pathways and suppresses pro-inflammatory responses by inhibiting NF-κB and MAPK activation, while promoting anti-inflammatory signalling via STAT6 and VDR-PPARγ axis. Deficiency in 1,25(OH)
2
D
3
is strongly associated with increased inflammation and oxidative stress in COPD correlating with increased disease severity. Conversely, restoring vitamin D3 levels reduces oxidative damage, suppresses pro-inflammatory gene expression, and improves alveolar macrophage function highlighting its therapeutic potential in modulating inflammation.
Journal Article
Brd4 Is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells
Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as \"readers\" of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells.
Human primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.
H2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters.
Oxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target.
Journal Article
Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease
There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on \"self\" proteins.
To determine the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins.
Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescence-activated cell sorter.
Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein.
Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.
Journal Article
Curcumin Restores Corticosteroid Function in Monocytes Exposed to Oxidants by Maintaining HDAC2
Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)- or oxidative stress-impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC(50) of approximately 30 nM and 200 nM, respectively. CSE caused a reduction in HDAC2 protein expression that was restored by curcumin. This decrease in HDAC2 protein expression was reversed by curcumin even in the presence of cycloheximide, a protein synthesis inhibitor. The proteasomal inhibitor, MG132, also blocked CSE-induced HDAC2 degradation, increasing the levels of ubiquitinated HDAC2. Biochemical and gene chip analysis indicated that curcumin at concentrations up to 1 muM propagates its effect via antioxidant-independent mechanisms associated with the phosphorylation-ubiquitin-proteasome pathway. Thus curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity induced by either CSE or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.
Journal Article
Cigarette Smoke Alters Chromatin Remodeling and Induces Proinflammatory Genes in Rat Lungs
Cigarette smoke-triggered inflammation is considered to play a central role in the development of chronic obstructive pulmonary disease by a mechanism that may involve enhanced proinflammatory gene transcription. Histone acetylation and deacetylation is a key regulator of the specificity and duration of gene transcription. Disruption in the nuclear histone acetylation:deacetylation balance (chromatin remodeling) may result in excessive transcription of specific proinflammatory genes in the lungs. In this study we show that cigarette smoke exposure results in an influx of inflammatory cells and chromatin modifications in rat lungs. This was associated with an increase in the active phosphorylated form of p38 mitogen-activated protein kinase concomitant with increased histone 3 phospho-acetylation, histone 4 acetylation, and increased DNA binding of the redox-sensitive transcription factor nuclear factor-kappaB, independent of inhibitory protein-kappaB degradation, and activator protein 1. We also observed decreased histone deacetylase 2 activity, which is due to protein modification by aldehydes and nitric oxide products present in cigarette smoke. Furthermore, we show that corticosteroid treatment has no effect on smoke-induced proinflammatory mediator release. These findings suggest a possible molecular mechanism by which cigarette smoke drives proinflammatory gene transcription and an inflammatory response in the lungs.
Journal Article
Cellular and molecular features of COVID-19 associated ARDS: therapeutic relevance
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support.
The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS.
Journal Article
Correction to: Research Cigarette Smoke Exposure Alters mSin3a and Mi-2α/β Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function
An amendment to this paper has been published and can be accessed via the original article.
Journal Article