Glucose Homeostasis in Relation to Neutrophil Mobilization in Smokers with COPD

Nikolaos Pournaras,1,2 Anders Andersson,3,4 Melissa A Kovach,1 Médea Padra,5 Karlhans F Che,1,2 Bettina Brundin,1 Shigemi Yoshihara,6 Steven Bozinovski,7 Sara K Lindén,5 Per-Anders Jansson,8 Magnus C Sköld,2,9 Ingemar Qvarfordt,3,8 Anders Lindén1,2 1Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Karolinska Severe COPD Center, Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden; 3COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden; 4COPD Center, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 5Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 6Pediatric Allergology and Respiratory Medicine, Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan; 7School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia; 8Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 9Division for Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenCorrespondence: Nikolaos Pournaras, Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden and Karolinska Severe COPD Center, Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden, Email nikolaos.pournaras@ki.sePurpose: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are common comorbidities in chronic obstructive pulmonary disease (COPD), but the underlying pathogenic mechanisms are poorly understood. Given that these morbidities all display increased neutrophil mobilization, the current study aimed to address whether glucose homeostasis relates to signs of neutrophil mobilization in COPD.Methods: The study population included healthy non-smokers (HNS) and long-term smokers without (LTS) and with COPD (LTS+COPD). No subject had T2DM or MetS. Serum cotinine was quantified to evaluate current smoking. Capillary blood glucose was measured after overnight fasting and during an oral glucose tolerance test (OGTT). Neutrophils were quantified in blood and bronchoalveolar lavage samples (BAL). The neutrophil-related cytokines IL-36α, -β and -γ were quantified (ELISA) along with IL-6, IL-8, INF-γ and CXCL10 (U-Plex®) in plasma and cell-free BAL fluid (BALF). In addition, we quantified neutrophil elastase (ELISA) and net proteinase activity (substrate assay) in BALF.Results: The LTS+COPD group had lower fasting glucose, greater change in glucose during OGTT and higher neutrophil concentrations in BAL and blood compared with HNS. Fasting glucose correlated in a positive manner with blood neutrophil concentration, forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) and FEV1 (% of predicted) in LTS+COPD. In this group, the concentration of IL-36α in BALF correlated in a negative manner with fasting glucose, blood neutrophil concentration and FEV1, while the CXCL10 concentration in BALF correlated in a negative manner with glucose at the end of OGTT (120 min). We observed no corresponding correlations for neutrophil elastase, net proteinase or gelatinase activity.Conclusion: In smokers with COPD, altered glucose homeostasis is associated with local and systemic signs of increased neutrophil mobilization, but not with local proteinases. This suggests that other specific aspects of neutrophil mobilization constitute pathogenic factors that affect glucose homeostasis in COPD.Keywords: granulocyte, elastase, IL-36, IP-10, BAL