| 1. |
- Mori, Michiko, et al.
(författare)
-
Small airway epithelial-C/EBPβ is increased in patients with advanced COPD.
- 2015
-
Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 16
-
Tidskriftsartikel (refereegranskat)abstract
- The expression of CCAAT/enhancer-binding protein (C/EBP)β in the small airway epithelium of COPD is unknown. C/EBPβ was assessed in peripheral lung tissue of non-smoking/smoking controls and patients with GOLD I-IV COPD by quantitative immunohistochemistry. The expression of C/EBPβ was decreased in smokers compared to never smokers. Furthermore, C/EBPβ was significantly elevated in advanced COPD vs. asymptomatic smokers, and the expression correlated to lung function decline. As C/EBPβ exerts pro-inflammatory effects in the context of cigarette smoke, the elevated C/EBPβ in advanced COPD may be an indication of a breakdown of regulatory mechanisms and excessive inflammation.
|
|
| 2. |
- Roos, Abraham B., et al.
(författare)
-
Increased IL-17RA and IL-17RC in End-Stage COPD and the Contribution to Mast Cell Secretion of FGF-2 and VEGF
- 2017
-
Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- Mast cells are accumulated in advanced chronic obstructive pulmonary disease (COPD), and interleukin (IL)-17 signaling plays a role in disease progression. The expression, localization and functional relevance of IL-17 receptor (R)A and IL-17RC was explored in COPD by immunodetection, and functional assays. IL-17RA and IL-17RC was increased in very severe COPD, and expressed by mast cells. Increased secretion of the pro-angiogenic basic fibroblast growth factor and vascular endothelial growth factor was observed in vitro-maintained mast cells stimulated with IL-17A. Expression of these mediators was confirmed in end-stage COPD. Thus, accumulation of mast cells in COPD may contribute to vascular remodeling.
|
|
| 3. |
- Roos, Abraham B
(författare)
-
Regulation of gene expression in pulmonary inflammation and differentiation : a role for C/EBP transcription factors
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CCAAT/enhancer-binding protein (C/EBP) transcription factors play essential roles in gene regulation. The lung-enriched isoform C/EBPα is known to inhibit proliferation, promote differentiation and stimulate gene expression characteristic of the mature differentiated pulmonary epithelium. C/EBPβ, also enriched in the lung, plays a role in cell differentiation and the regulation of inflammatory and host defense genes in several organs. The activity of C/EBPβ is decreased in smokers with chronic obstructive pulmonary disease (COPD), indicating a role in COPD pathogenesis. The objective of this thesis was to investigate the unique or overlapping roles of C/EBPα and C/EBPβ in lung epithelial differentiation, and to assess the contribution of C/EBPβ in regulating pulmonary inflammation. To investigate unique vs. overlapping roles of C/EBPα and C/EBPβ in the lung, the pulmonary phenotype of mice lacking C/EBPα (CebpaΔLE mice), C/EBPβ (CebpbΔLE mice) or both C/EBPα and C/EBPβ (CebpaΔLE; CebpbΔLE mice) specifically in the lung epithelium, all generated by SFTPC-Cre mediated excision, was investigated. Cell culture experiments suggested that C/EBPα and C/EBPβ bind the same elements within a lung-specific promoter, and that their functions are partially overlapping. Pre-natal CebpaΔLE mice and CebpaΔLE; CebpbΔLE mice displayed immature lungs similar to the lungs of premature infants, and CebpaΔLE; CebpbΔLE mice exhibited even more impaired airway epithelial cell differentiation than the CebpaΔLE mice. The proportion of CebpaΔLE mice that survived and reached adulthood spontaneously developed a majority of the histopathological hallmarks of COPD, possibly caused by infiltrating inflammatory cells – similar to what is observed in COPD and what is mechanistically proposed to drive COPD pathogenesis. These findings are indicative of a relationship between immature lungs at birth, C/EBPs and the development of inflammatory lung disease. Considering the previous documentation of decreased airway epithelial C/EBPβ activity in smokers with COPD, C/EBPβ could have a role in COPD pathogenesis. The role of C/EBPβ in regulating inflammatory and innate immune responses in the lung was on this account investigated by employing a translational approach encompassing clinical samples as well as in vitro and in vivo experiments. CEBPB was significantly down-regulated in the airway epithelium of both current and former smokers compared to never-smokers, and in cigarette smoke extract-treated primary human airway epithelial cells in vitro, suggesting that C/EBPβ plays a role in smoking-induced disease. Supporting this, inhibition of CEBPB in human airway cells in vitro resulted in a compromised inflammatory response to smoke. Moreover, cigarette smoke-exposed CebpbΔLE mice displayed reduced respiratory neutrophilia and induction of inflammatory mediators, including the neutrophil chemoattractant Groa, compared to smoke- exposed controls. LPS-challenged CebpbΔLE mice also exhibited blunted respiratory neutrophilia and lower pulmonary expression of Groa, compared to LPS-challenged control littermates. In addition, suppression of LPS-induced neutrophilia and inflammatory gene expression by formoterol, a long acting β2-adrenoceptor agonist used in treatment of COPD, was impaired in CebpbΔLE mice. C/EBP transactivation was increased by treatment with formoterol in vitro, possibly through a β2-adrenoceptor and cAMP-dependent mechanism. This demonstrates that both inflammatory as well as anti-inflammatory stimuli involve regulation of gene transcription by C/EBPβ. Taken together, these findings demonstrate that C/EBPα and C/EBPβ play pivotal and partly overlapping roles in airway epithelial differentiation, and that C/EBP and the lung epithelium orchestrates inflammatory responses as well as anti-inflammatory signaling by β2-adrenoceptor agonists in the lung. Thus, C/EBPs may influence tissue regeneration in lung homeostasis and disease as well as inflammatory and anti-inflammatory signaling, and are potential contributors to COPD pathogenesis.
|
|
| 4. |
|
|
| 5. |
- Roos, Abraham, et al.
(författare)
-
IL-17A is Elevated in End-stage COPD and Contributes to Cigarette Smoke-induced Lymphoid Neogenesis.
- 2015
-
Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 191:11, s. 1232-1241
-
Tidskriftsartikel (refereegranskat)abstract
- End-stage chronic obstructive pulmonary disease (COPD) is associated with an accumulation of pulmonary lymphoid follicles. Interleukin (IL)-17A is implicated in COPD and pulmonary lymphoid neogenesis in response to microbial stimuli. We hypothesized that IL-17A is increased in peripheral lung tissue during end-stage COPD and also directly contributes to cigarette smoke-induced lymphoid neogenesis.
|
|
| 6. |
|
|
| 7. |
- Shen, Pamela, et al.
(författare)
-
Cigarette smoke attenuates the nasal host response to Streptococcus pneumoniae and predisposes to invasive pneumococcal disease in mice.
- 2016
-
Ingår i: Infection and Immunity. - 1098-5522. ; 84:5, s. 1536-1547
-
Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae is a leading cause of invasive bacterial infections, with nasal colonization an important first step for disease. While cigarette smoking is a strong risk factor for invasive pneumococcal disease, underlying mechanisms remain unknown. This is partly due to a lack of clinically relevant animal models investigating nasal pneumococcal colonization in the context of cigarette smoke exposure. We present a model of nasal pneumococcal colonization in cigarette smoke-exposed mice and document, for the first time, that cigarette smoke predisposes to invasive pneumococcal infection and mortality in an animal model. Cigarette smoke increased the risk of bacteraemia and meningitis without prior lung infection. Mechanistically, deficiency in IL-1α or PAFR, an important host receptor thought to bind and facilitate pneumococcal invasiveness, did not rescue cigarette smoke-exposed mice from invasive pneumococcal disease. Importantly, we observed cigarette smoke to attenuate nasal inflammatory mediator expression, particularly that of neutrophil recruiting chemokines, normally elicited by pneumococcal colonization. Smoking cessation during nasal pneumococcal colonization rescued nasal neutrophil recruitment and prevented invasive disease in mice. We propose that cigarette smoke predisposes to invasive pneumococcal disease by suppressing inflammatory processes of the upper respiratory tract. Given that smoking prevalence remain high worldwide, these findings are relevant to the continued efforts to reduce invasive pneumococcal disease burden.
|
|
| 8. |
|
|
| 9. |
- Kanai, M, et al.
(författare)
-
- 2023
-
swepub:Mat__t
|
|
