Phospho-p38 MAPK Expression in COPD Patients and Asthmatics and in Challenged Bronchial Epithelium

Caramori³

et al. 2017

Eur Respir J

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Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of ,, and was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4 and CD8 cells and airflow obstruction. NOD1 expression correlated with CD8 cells. The bronchial load of was directly correlated, but inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and bacterial load, may play a role in the pathogenesis of COPD.

Section: Inflammatory Cells In the Bronchial Biopsiesmentioning

confidence: 91%

Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression

Stefano

Caramori³

et al. 2017

Eur Respir J

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“…Investigations of intracellular molecular signal mechanisms showed that activation of MAPK/NF-κB signal pathways regulates cellular events like differentiation, proliferation, apoptosis and production of pro-inflammatory mediators as well as expression of GPCR in airways (Damera et al, 2012;Gerthoffer and Singer, 2003). In asthmatic patients, there are significant levels of phosphorylated ERK1/2 and p38 MAPK that correlate to the severity of airway disease ( Liu et al, 2008;Vallese et al, 2015). Bradykinin induced the differentiation of normal human lung fibroblasts into myofibroblasts (α-smooth muscle actin [α-SMA] + cells) via bradykinin B2 receptor activation (Vancheri et al, 2005).…”

Section: Bradykinin and Matrix-related Airway Remodellingmentioning

confidence: 99%

Bradykinin in asthma: Modulation of airway inflammation and remodelling

European Journal of Pharmacology

Folkerts

Folino

et al. 2018

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Bradykinin, a pro-inflammatory molecule, and its related peptides have been studied for their effects on acute reactions in upper and lower airways, where they can be synthesised and metabolized after exposure to different stimuli including allergens and viral infection. Bradykinin B and B receptors are constitutively expressed in the airways on several residential and/or immune cells. Their expression can also be induced by inflammatory mediators, usually associated with eosinophil and neutrophil recruitment, such as IL-4, IL-13, TNF-α, IL-6 and IL-8, via intracellular MAPK and NF-κB signalling. In turn, the latters up-regulate both bradykinin receptors. Bradykinin activates epithelial/endothelial and immune cells, neurons and mesenchymal cells (such as fibroblasts, myofibroblasts and smooth muscle cells), which are implicated in the development of airway chronic inflammation, responsiveness and remodelling (a major feature of severe asthma). This review highlights the role of bradykinin and its receptors in respect to chronic inflammatory response involving eosinophils/neutrophils and to vascular/matrix-related airway remodelling in asthmatic airways. This scenario is especially important for understanding the mechanisms involved in the pathogenesis of eosinophilic and/or neutrophilic asthma and hence their therapeutic approach.

“…In our knowledge, data on lung fibroblasts or epithelial cells challenged with radial ESW are not disposable. A second option could be the intratracheal administration of adipose-derived stem cells pretreated with ESW [22,23,48] in the attempt to improve the alveolar septa reparative response in mice with experimentally induced emphysema.…”

Section: Discussionmentioning

confidence: 99%

Extracorporeal Shock Waves Increase Markers of Cellular Proliferation in Bronchial Epithelium and in Primary Bronchial Fibroblasts of COPD Patients

Stefano

Frairia

Canadian Respiratory Journal

et al. 2020

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Chronic obstructive pulmonary disease (COPD) is due to structural changes and narrowing of small airways and parenchymal destruction (loss of the alveolar attachment as a result of pulmonary emphysema), which all lead to airflow limitation. Extracorporeal shock waves (ESW) increase cell proliferation and differentiation of connective tissue fibroblasts. To date no studies are available on ESW treatment of human bronchial fibroblasts and epithelial cells from COPD and control subjects. We obtained primary bronchial fibroblasts from bronchial biopsies of 3 patients with mild/moderate COPD and 3 control smokers with normal lung function. 16HBE cells were also studied. Cells were treated with a piezoelectric shock wave generator at low energy (0.3 mJ/mm2, 500 pulses). After treatment, viability was evaluated and cells were recultured and followed up for 4, 24, 48, and 72 h. Cell growth (WST-1 test) was assessed, and proliferation markers were analyzed by qRT-PCR in cell lysates and by ELISA tests in cell supernatants and cell lysates. After ESW treatment, we observed a significant increase of cell proliferation in all cell types. C-Kit (CD117) mRNA was significantly increased in 16HBE cells at 4 h. Protein levels were significantly increased for c-Kit (CD117) at 4 h in 16HBE (p < 0.0001) and at 24 h in COPD-fibroblasts (p = 0.037); for PCNA at 4 h in 16HBE (p = 0.046); for Thy1 (CD90) at 24 and 72 h in CS-fibroblasts (p = 0.031 and p = 0.041); for TGFβ1 at 72 h in CS-fibroblasts (p = 0.038); for procollagen-1 at 4 h in COPD-fibroblasts (p = 0.020); and for NF-κB-p65 at 4 and 24 h in 16HBE (p = 0.015 and p = 0.0002). In the peripheral lung tissue of a representative COPD patient, alveolar type II epithelial cells (TTF‐1+) coexpressing c-Kit (CD117) and PCNA were occasionally observed. These data show an increase of cell proliferation induced by a low dosage of extracorporeal shock waves in 16HBE cells and primary bronchial fibroblasts of COPD and control smoking subjects.