Airway Epithelial Cell Function and Respiratory Host Defense in Chronic Obstructive Pulmonary Disease

Pathogenesis and treatment of chronic pulmonary disease

Repairing damaged lungs using regenerative therapy

There is an urgent need for better treatment of lung diseases that are a major cause of morbidity and mortality worldwide. This urgency is illustrated by the current COVID-19 health crisis. Moderate-to-extensive lung injury characterizes several lung diseases, and not only therapies that reduce such lung injury are needed but also those that regenerate lung tissue and repair existing lung injury. At present, such therapies are not available, but as a result of a rapid increase in our understanding of lung development and repair, lung regenerative therapies are on the horizon. Here, we discuss existing targets for treatment, as well as novel strategies for development of pharmacological and cell therapy-based regenerative treatment for a variety of lung diseases and clinical studies. We discuss how both patient-relevant in vitro disease models using innovative culture techniques and other advanced new technologies aid in the development of pulmonary regenerative medicine.Pathogenesis and treatment of chronic pulmonary disease

Impact of the local inflammatory environment on mucosal vitamin D metabolism and signaling in chronic inflammatory lung diseases

Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. The active vitamin D metabolite, 1,25-dihydroxy-vitamin D (1,25(OH)(2)D), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. These mechanisms may partly explain its protective role against infections and exacerbations in COPD and asthma patients. The respiratory mucosa is an important site of local 1,25(OH)(2)D synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. As a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., COPD and asthma, may modulate the protective actions of 1,25(OH)(2)D. Here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin D metabolism and local responses to 1,25(OH)(2)D in both immune- and epithelial cells. We furthermore discuss potential consequences of disturbed local levels of 25(OH)D and 1,25(OH)(2)D for chronic lung diseases. Additional insight into the relationship between disease-associated mechanisms and local effects of 1,25(OH)(2)D is expected to contribute to the design of future strategies aimed at improving local levels of 1,25(OH)(2)D and signaling in chronic inflammatory lung diseases.Pathogenesis and treatment of chronic pulmonary disease

The course of A alpha Val541 as a proteinase 3 specific neo-epitope after alpha-1-antitrypsin augmentation in severe deficient patients

In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide A alpha Val541, compared with healthy controls. Here, we analyzed the course of A alpha Val541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure A alpha Val541 in plasma and applied population pharmacokinetic modeling for AAT. The median A alpha Val541 plasma level before treatment was 140.2 nM (IQR 51.5-234.8 nM)). In five patients who received AAT for the first time, A alpha Val541 levels decreased to 20.6 nM (IQR 5.8-88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31-35.0 nM). In 9 of 10 patients, A alpha Val541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7-30.1 nM). At 7-14 days after treatment, A alpha Val541 levels started to increase again in all patients. Our results show that fibrinopeptide A alpha Val541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.Pathogenesis and treatment of chronic pulmonary disease

ADAM17 and EGFR regulate IL-6 receptor and amphiregulin mRNA expression and release in cigarette smoke-exposed primary bronchial epithelial cells from patients with chronic obstructive pulmonary disease (COPD)

Aberrant activity of a disintegrin and metalloprotease 17 (ADAM17), also known as TACE, and epidermal growth factor receptor (EGFR) has been suggested to contribute to chronic obstructive pulmonary disease (COPD) development and progression. The aim of this study was to investigate the role of these proteins in activation of primary bronchial epithelial cells differentiated at the air–liquid interface (ALI-PBEC) by whole cigarette smoke (CS), comparing cells from COPD patients with non-COPD. CS exposure of ALI-PBEC enhanced ADAM17-mediated shedding of the IL-6 receptor (IL6R) and the EGFR agonist amphiregulin (AREG) toward the ba

Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

Pathogenesis and treatment of chronic pulmonary disease

Functional characterisation of bone marrow-derived mesenchymal stromal cells from COPD patients

ABSTRACT Autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) are evaluated forclinical use in chronic obstructive pulmonary disease (COPD) patients, but it is unclear whether COPDaffects BM-MSCs.To investigate this, BM-MSCs from nine COPD patients and nine non-COPD age-matched controls werecompared with regard to immunophenotype, growth and differentiation potential, and migration capacity.Other functional assays included the response to pro-inflammatory stimuli and inducers of the nuclearfactor (erythroid derived 2)-like 2 antioxidant response element (Nrf2-ARE) pathway, and effects on NCIH292airway epithelial cells.No significant differences were observed in terms of morphology, proliferation and migration, except forincreased adipocyte differentiation potential in the COPD group. Both groups were comparable regardingmRNA expression of growth factors and inflammatory mediators, and in their potential to induce mRNAexpression of epidermal growth factor receptor ligands in NCI-H292 airway epithelial cells. MSCs fromCOPD patients secreted more interleukin-6 in response to pro-inflammatory stimuli. Activation of the Nrf2-ARE pathway resulted in a comparable induction of mRNA expression of four target genes, but theexpression of the NAD(P)H:quinone oxidoreductase 1 gene NQO1 was lower in MSCs from COPD patients.The observation that MSCs from COPD patients are phenotypically and functionally comparable tothose from non-COPD controls implies that autologous MSCs can be considered for use in the setting ofclinical trials as a treatment for COPD.Pathogenesis and treatment of chronic pulmonary disease