Background Matrix metalloproteinase (MMP)-12 has been implicated in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and asthma. The influence of disease severity on sputum ...MMP-12 concentrations and activity is not known. Objectives We sought to examine the relationship between disease severity assessed by means of lung function and computed tomography (CT) and induced sputum MMP-12 concentrations and activity in patients with asthma and COPD. Methods In 208 subjects (109 asthmatic patients, smokers and never smokers, mild, moderate, and severe; 53 patients with COPD, smokers and exsmokers, mild, moderate, and severe; and 46 healthy control subjects, smokers and never smokers), we measured induced sputum MMP-12 concentrations (ELISA) and enzyme activity (fluorescence resonance energy transfer), sputum cell MMP12 mRNA expression (quantitative PCR qPCR), diffusing capacity for carbon monoxide (D lco ), and CT assessment of emphysema (percentage of low-attenuation areas at less −950 Hounsfield units). Results Sputum MMP-12 concentrations are greater in patients with COPD and smokers with asthma than in healthy nonsmokers ( P = .003 and P = .035, respectively) but similar to those seen in healthy smokers. In patients with COPD, disease severity, when measured by means of CT-assessed emphysema, but not by means of spirometry or D lco values, is directly associated with sputum MMP-12 concentrations and activity. In the asthma groups there is no significant association between disease severity and sputum MMP-12 concentrations or activity. Conclusions Sputum MMP-12 concentrations and activity in patients with COPD are directly associated with the extent of emphysema measured by means of CT. This finding supports a role for MMP-12 in the pathogenesis of COPD and might suggest that blocking MMP-12 activity in patients with COPD could prevent the further development of emphysema.
Parturition is associated with myometrial and cervical inflammation. The causes and consequences of this inflammatory response are not clear. Mast cells (MCs) are important inducers of allergic and ...non-allergic inflammation, and their secreted products can induce myometrial contractions. Thus, mast cell activation has been hypothesized to have a role in initiating labor and/or driving labor-associated inflammation. We report that small numbers of MCs expressing chymase and tryptase are present in the myometrium and cervix of pregnant women. Labor did not lead to any change in mast cell abundance in these tissues, but was associated with reduced expression of the mast-cell regulator FcεR1A, indicative of a change in mast cell properties. This coincided with contraction-dependent myocyte production of interleukin-10 (IL-10), a known suppressor of FcεR1A expression. MCs were also found in the uterine horn and cervical region of pregnant C57BL/6 mice, increasing in number in the cervix, but not the myometrium, with labor. As expected, these cells were absent from mast-cell-deficient Kit(W-sh) mice. Nonetheless, pregnant Kit(W-sh) mice showed no defects in the timing of labor induction or in the upregulation of leukocyte markers during labor. Thus, MCs are present in the uterus and cervix of humans and mice, and our mouse studies suggest that they do not have a vital role in the induction of labor, or in the promotion of labor-associated inflammation.
Abstract Airway hyper-responsiveness associated with asthma is mediated by airway smooth muscle cells (SMCs) and has a complicated etiology involving increases in cell contraction and proliferation ...and the secretion of inflammatory mediators. Although these pathological changes are diverse, a common feature associated with their regulation is a change in intracellular Ca2+ concentration (Ca2+ i ). Because the Ca2+ i itself is a function of the activity and expression of a variety of ion channels, in both the plasma membrane and sarcoplasmic reticulum of the SMC, the modification of this ion channel activity may predispose airway SMCs to hyper-responsiveness. Our objective is to review how ion channels determine the Ca2+ i and influence the function of airway SMCs and emphasize the potential of ion channels as sites for therapeutic approaches to asthma.
The immune system Howell, Malcolm; Shepherd, Malcolm
Anaesthesia and intensive care medicine,
August 2021, 2021-08-00, Volume:
22, Issue:
8
Journal Article
Peer reviewed
This article intends to provide an up-to-date overview of the relevant physiology required to pass the FRCA. The immune system is our defence against pathogens. This includes the recognition of ...non-self organisms, and protection through a variety of non-specific and highly specific mechanisms. Failure of the immune system leads to immunodeficiency or immunopathology; either may be catastrophic for the host.
Published information on the effectiveness of bronchial thermoplasty (BT) for severe asthma in ‘real life’ patients is limited. We compared safety and efficacy outcomes 12 months post procedure in 10 ...clinic patients and 15 patients recruited to clinical trials of BT at the same centre. Baseline asthma severity was greater in the clinic group. Adverse events were similar. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients.
The expression profile of a panel of 15 cAMP phosphodiesterase isoforms was determined for inflammatory cell types of relevance to chronic obstructive pulmonary disease (COPD). In particular, the ...expression profiles for bronchoalveolar macrophages, peripheral blood monocytes, T lymphocytes, and neutrophils from smokers with and without COPD were compared. The phosphodiesterase expression profile was also analyzed for peripheral blood monocytes, T lymphocytes, and neutrophils from nonsmokers and compared with smokers. Qualitative RT-PCR identified transcripts for PDE4A10, PDE4A7, PDE4B1, PDE4B2, PDE4D1, and PDE4D2 isoforms as well as transcripts for both PDE3B and PDE7A in T cells, monocytes, and macrophages in all subjects. Transcripts for PDE4B3 and PDE4D4 were not observed in any of the cell types investigated. PDE4C was detected in all cells analyzed except for T cells. The long PDE4A4, PDE4D3, and PDE4D5 isoforms exhibited cell type-specific expression patterns. Semiquantitative and real-time quantitative RT-PCR were used to analyze differential expression between disease states and between cell types. PDE4A4 was found significantly upregulated in lung macrophages from smokers with COPD when compared with control smokers. Furthermore, PDE4A4 as well as PDE4B2 transcripts were detected in higher amounts in peripheral blood monocytes of smokers when compared with nonsmokers. Finally, PDE4D5 and PDE4C were differentially regulated in lung macrophages when compared with monocytes of the same subjects, irrespective of the disease state. The data obtained suggest that PDE4A4 may be relevant as a macrophage-specific anti-inflammatory target for COPD.
Monocytes and macrophages provide key targets for the action of novel anti‐inflammatory therapeutics targeted at inhibition of PDE4 cAMP‐specific phosphodiesterases.
PDE4 enzymes provide the dominant ...cAMP phosphodiesterase activity in U937 human monocytic cells.
Differentiation of U937 monocytic cells to a macrophage‐like phenotype causes a marked reduction in total cellular PDE4 activity.
Monocytic U937 cells express the long PDE4A4, PDE4D5 and PDE4D3 isoforms plus the short PDE4B2 isoform. Differentiation of U937 cells to a macrophage‐like phenotype causes a marked downregulation of PDE4D3 and PDE4D5, elicits a marked upregulation of PDE4B2 and induces the novel PDE4A10 long isoform. Comparable patterns are found in human peripheral blood monocytes and macrophages differentiated from them.
Immunopurification of PDE4 subfamilies identifies long PDE4D isoforms as providing the major PDE4 activity in U937 monocytic cells.
In U937 macrophage‐like cells, the activity of the short PDE4B2 isoform predominates.
No indication of either the expression or induction of PDE4C was evident.
Activation of ERK exerts an inhibitory effect on total PDE4 activity in monocytic U937 cells, where the activity of long PDE4 isoforms predominates.
The effect of ERK activation is switched to one of overall stimulation of total PDE4 activity in macrophage U937 cells, where the activity of the short PDE4B2 isoform predominates.
The profound differentiation‐induced changes in PDE4 isoform profile identified here suggests that the development of inhibitors specific for particular PDE4 isoforms may allow for selective effects on monocytes and macrophages to be achieved.
British Journal of Pharmacology (2004) 142, 339–351. doi:10.1038/sj.bjp.0705770
The immune system Howell, Malcolm; Shepherd, Malcolm
Anaesthesia and intensive care medicine,
October 2018, 2018-10-00, Volume:
19, Issue:
10
Journal Article
Peer reviewed
This article intends to provide an up-to-date overview of the relevant physiology required to pass the FRCA. The immune system is our defence against pathogens. This includes the recognition of ...non-self organisms, and protection through a variety of non-specific and highly specific mechanisms. Failure of the immune system leads to immunodeficiency or immunopathology either may be catastrophic for the host.
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