Overview
Background: There is wide variety in lung disease phenotype for the delta F508 (homozygous) genotype. A leukocyte driven inflammation is most important for the pathogenesis of pulmonary disease in CF. Blood cytokines correlate negatively with pulmonary function in delta F508 homozygous patients. Gap junction proteins might be of importance for the influx of blood cells into the lung and may influence the course of pulmonary inflammation.
Aims: To assess the relationship between gap junction proteins alpha 1 (GJA1/Connexin 43) and alpha 4 (GJA4/connexin 37) genotypes and clinical disease phenotype.
Methods:Patients homozygous for delta F508 get recruited from the CF centres of Bonn, Frankfurt and Amsterdam. Sequence analysis is performed for connexin 43 and 37. Clinical disease is assessed longitudinally over 3 years by pulmonary function tests (FEV1 (forced expiratory volume in one second), FVC (=(forced vital capacity), FEF75 % (Forced expiratory flow at 75% of the pulmonary volume) pred), BMI (percentiles), P. aeruginosa colonization, diabetes mellitus and survival to end-stage CF lung disease (death or lung transplantation).
Description
Progressive pulmonary destruction is the major cause of morbidity and mortality in human subjects with cystic fibrosis. Many studies could not find an association between delta F 508 and severity of pulmonary disease . The most important factor in CF lung disease is an inflammation driven by leukocytes and cytokines. The investigators have provided evidence in former studies that cytokines (Interleukin-8 (IL-8), tumour necrosis factor (TNF) alpha, Lipopolysaccahride binding protein (LBP), transforming growth factor (TGF) )measured in blood correlate negatively with lung function in delta 508 homozygous patients.
The question arises, what other factors influence recruitment of proinflammatory leukocytes from blood capillaries into the lung .
Connexins are a family of transmembrane proteins, which oligomerize into hexameric structures to form a hemichannel (connexon) and ultimately pair with a partner hemichannel in an adjacent cell to form gap junction intercellular communication channels (GJIC) . There is evidence of expression of connexin 37 (=gap junction protein A4 (GJA4)) on macrophages in humans. Moreover there is evidence of expression of connexin 37 on vascular endothelia in humans . Connexin 37 is expressed on human neutrophils . Pulmonary disease in CF is dominated by a leukocyte driven inflammation. GAP junction proteins might be of importance for the influx of blood cells into the lung. In this regard, the hypothesis was that Cx37 or Cx43 genotypes have an impact on clinical disease phenotype in CF patients homozygous for delta F508.
Eligibility
Inclusion Criteria:
Homozygosity for delta F 508
Exclusion Criteria:
treatment with systemic steroids 14 days preceding this trial, participation in another study within the past 30 days, treatment with Orkambi or status after lung transplantation (for assessment of all parameters except survival).