Mark Gjomarkaj

Background: Obesity‐related asthma (OBA) is a distinct asthma phenotype, with increased severity. Adipokine release from excessive adipose tissue is suggested to be a key feature of OBA pathophysiology. However, it is unclear how the clinical characteristics of severe asthma associate with adipokine mediators. We examined systemic adipokine levels and evaluated relationships with disease severity, weight, sex, and steroid treatment in asthma. Methods: A multiplex immunoassay for nine adipokines with proposed involvement in obesity‐related inflammation (adiponectin, adipsin, BAFF, chemerin, FGF‐21, leptin, lipocalin‐2/NGAL, osteonectin and resistin) was designed. Plasma adipokines were measured in 127 patients with mild‐to‐moderate asthma (MMA) or severe asthma (SA) from the European BIOAIR cohort at baseline and after a controlled 2‐week oral corticosteroid (OCS) intervention. Results: Leptin and chemerin were significantly increased in patients with SA vs. MMA. Leptin, adiponectin, adipsin, and NGAL were affected by sex, whereas leptin and adipsin were strongly affected by weight. OCS increased leptin and adiponectin, decreased adipsin and BAFF, and did not affect osteonectin, resistin, or chemerin. No adipokines showed positive associations with exhaled NO, blood or sputum eosinophils, although certain correlations with serum CRP, blood, and sputum neutrophils were observed. Conclusions: Overall, we observe variable relationships between the nine adipokines, obesity and asthma severity. There were no relationships between adipokine levels and type‐2 airway inflammation, yet associations with systemic neutrophilic inflammation were seen. Although one adipokine, chemerin, was independently associated with asthma severity, deciphering the role of adipokines in OBA is complex due to the influence of sex, BMI, and OCS.

The exposure to risk factors, such as cigarette smoke and air pollution (containing metabolic oxidants and toxic substances), leading to cellular and molecular alterations, promotes the development of lung cancer at multiple stages. The antioxidant defence system plays a critical role in counteracting the mechanisms of oxidative stress. In physiological conditions, the balance between pro-oxidant and antioxidant species is critically important for the correct performance of cellular functions. Its imbalance is accompanied by the onset and progression of various pathologic states, including lung cancer. Cell signalling pathways and non-coding RNAs play a crucial role in the mechanisms of carcinogenesis and in the development of resistance to conventional therapeutic treatments. The interplay between the oxidant/antioxidant system, transcription factors, and non-coding RNAs is involved in the development and in the pathogenesis of lung cancer. This review provides a comprehensive resource for researchers and clinicians to better understand this intricate system and its cellular interactions, with the aim of disseminating the knowledge of the mechanisms involved in both cancer development and the development of new anti-cancer therapeutic strategies. A thorough understanding of the interplay between oxidative stress mechanisms, the activity of transcription factors, and non-coding RNAs could improve the efficacy of drug treatments and open new pharmacological perspectives for the control of inflammation and disease progression in lung cancer.

IL-17A drives inflammation and oxidative stress, affecting the progression of chronic lung diseases (asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis). Oleuropein (OLP) is a polyphenolic compound present in olive oil and widely included in the Mediterranean diet. It exerts antioxidant and anti-inflammatory activities, oxidative stress resistance, and anticarcinogenic effects with a conceivable positive impact on human health. We hypothesized that OLP positively affects the mechanisms of oxidative stress, apoptosis, DNA damage, cell viability during proliferation, and cell growth in alveolar epithelial cells and tested its effect in a human alveolar epithelial cell line (A549) in the presence of IL-17A. Our results show that OLP decreases the levels of oxidative stress (Reactive Oxygen Species, Mitochondrial membrane potential) and DNA damage (H2AX phosphorylation-ser139, Olive Tail Moment data) and increases cell apoptosis in A549 cells exposed to IL-17A. Furthermore, OLP decreases the number of viable cells during proliferation, the migratory potential (Scratch test), and the single cell capacity to grow within colonies as a cancer phenotype in A549 cells exposed to IL-17A. In conclusion, we suggest that OLP might be useful to protect lung epithelial cells from oxidative stress, DNA damage, cell growth, and cell apoptosis. This effect might be exerted in lung diseases by the downregulation of IL-17A activities. Our results suggest a positive effect of the components of olive oil on human lung health.

Rationale: Asthma phenotyping requires novel biomarker discovery.Objectives: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs).Methods: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED.Results: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SAversusMMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.Conclusions: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

I. Brusca ignbr@libero.it 1 S. Graci 2 M. Barrale 1 G. Cammilleri 2 M. Zarcone 3 R. Onida 1 A. Costa 2 V. Ferrantelli 2 M.D. Buscemi 2 C.G. Uasuf 4 M....

Maurizio Vignola was a superb and innovative researcher, who wrote seminal papers on the biology of airway epithelium in asthma. Inflammation and remodelling were the main topics of his research, mostly conducted in biopsy specimens from patients with asthma of variable severity, encompassing the entire spectrum of the disease from mild to severe asthma. His observations contributed to define the biology of asthma as we know it today, and opened the way to the personalised treatment of asthma. His group has successfully continued to investigate the biology and clinical aspects of bronchial asthma, with major interest in the clinical use of biomarkers to monitor disease activity, and in the development of new therapeutic perspectives. This review summarises the latest work on these topics proudly conducted by Maurizio's closest collaborators. The results indicate significant progress in our understanding of asthma in the last 10 years, in particular increased knowledge of the complex interaction between inflammatory and remodelling pathways, improved recognition of biological and clinical asthma phenotypes, and development of new treatment strategies, especially for patients with severe corticosteroid-resistant asthma.

Summary: Leukotriene B₄(LTB₄) is a neutrophil chemotactic molecule with important involvement in the inflammatory responses of chronic obstructive pulmonary disease (COPD). Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke, the major risk factor forCOPD. In this study we have explored whether cigarette smoke extracts (CSE) or soluble mediators present in distal lung fluid samples (mini‐bronchoalveolar lavages) from smokers alter the expression of theLTB₄receptor 2 (BLT2) and peroxisome proliferator‐activated receptor‐α (PPAR‐α) in bronchial epithelial cells. We also evaluated the effects ofCSEon the expression of intercellular adhesion molecule 1 (ICAM‐1) and on the binding of signal transducer and activator of transcription 1 (STAT‐1) toICAM‐1 promoter as well as the adhesiveness of neutrophils to bronchial epithelial cells.CSEand mini‐bronchoalveolar lavages from smokers increasedBLT2 andICAM‐1 expression as well as the adhesiveness of neutrophils to bronchial epithelial cells and decreasedPPAR‐α expression.CSEinduced the activation ofSTAT‐1 and its binding toICAM‐1 promoter. These findings suggest that, in bronchial epithelial cells,CSEpromote a prevalent induction of pro‐inflammatoryBLT2 receptors and activate mechanisms leading to increased neutrophil adhesion, a mechanism that contributes to airway neutrophilia and to tissue damage.