476 research outputs found
Does upregulated host cell receptor expression provide a link between bacterial adhesion and chronic respiratory disease?
Expression of the platelet-activating factor receptor is upregulated in the respiratory epithelium of smokers and chronic obstructive pulmonary disease patients. We have recently determined that increased expression of PAFr correlates with higher levels of adhesion to human bronchial epithelial cells by non-typable Haemophilus influenzae and Streptococcus pneumoniae which are major bacterial pathogens in acute exacerbations of COPD. In addition, we found that a PAFr antagonist decreased the adhesion of both respiratory bacterial pathogens to non-cigarette exposure control levels. This highlights the possibility that epithelial receptors, that are upregulated in response to cigarette smoke, could be targeted to specifically block chronic bacterial infections of the lower respiratory tract. In this commentary, we explore the question of whether adhesion to a temporally-upregulated host receptor is a common event in chronic bacterial disease, and as such, could represent a putative therapeutic target for blocking infection by respiratory and other pathogens
The Underappreciated Role of Epithelial Mesenchymal Transition in Chronic Obstructive Pulmonary Disease and Its Strong Link to Lung Cancer.
The World Health Organisation reported COPD to be the third leading cause of death globally in 2019, and in 2020, the most common cause of cancer death was lung cancer; when these linked conditions are added together they come near the top of the leading causes of mortality. The cell-biological program termed epithelial-to-mesenchymal transition (EMT) plays an important role in organ development, fibrosis and cancer progression. Over the past decade there has emerged a substantial literature that also links EMT specifically to the pathophysiology of chronic obstructive pulmonary disease (COPD) as primarily an airway fibrosis disease; COPD is a recognised strong independent risk factor for the development of lung cancer, over and above the risks associated with smoking. In this review, our primary focus is to highlight these linkages and alert both the COPD and lung cancer fields to these complex interactions. We emphasise the need for inter-disciplinary attention and research focused on the likely crucial roles of EMT (and potential for its inhibition) with recognition of its strategic place mechanistically in both COPD and lung cancer. As part of this we discuss the future potential directions for novel therapeutic opportunities, including evidence-based strategic repurposing of currently used familiar/approved medications
Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control
Formoterol is a longāacting beta2āadrenoceptor agonist (LABA) used for treatment of asthma and exerciseāinduced bronchoconstriction. Formoterol is usually administered as a racemic (racā) mixture of (R,R)ā and (S,S)āenantiomers. While formoterol is restricted by the World AntiāDoping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 Ī¼g/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)āformoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 Ī¼g inhaled dose of racāformoterol. Urine was collected over 24āhours and analysed by enantioselective UPLCāMS/MS assay. Total (free drug plus conjugated metabolite) median (mināmax) racāformoterol urine levels following inhalation were 1.96(1.05ā13.4) ng/mL, 1.67(0.16ā9.67) ng/mL, 0.45(0.16ā1.51) ng/mL, 0.61(0.33ā0.78) ng/mL, and 0.17(0.08ā1.06) ng/mL at 2, 4, 8, 12 and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)āformoterol (around 30ā60% of total) compared to (S,S)āformoterol (0ā30%). There was clear evidence of interāindividual enantioselectivity observed in the ratios of (R,R):(S,S)āformoterol, where (S,S)ā was predominant in free formoterol, and (R,R)ā predominant in the conjugated metabolite. In conclusion, racāformoterol delivered by inhalation exhibits enantioselective elimination in urine following single dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2āagonist chiral switch products such as (R,R)āformoterol, and total hydrolysed racāformoterol is warranted to account for interāindividual differences in enantioselective glucuronidation
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