Kistik Fibrozis Hastalarının Alevlenme ve Remisyon Dönemleri Plazma Sfingomyelin ve Seramid Düzeylerinin Sıvı Kromatografisi-Kütle Spektrometresi ile Belirlenmesi ve Bazı İnflamasyon Belirteçleriyle İlişkisinin İncelenmesi

Abstract

Cystic fibrosis (CF) is the most common autosomal recessive genetic disorder of caucaisan population. Despite the multisystemic involvement in CF, increased mucus viscosity in the lungs, deterioration of mucociliary clearance and consequent chronic lung infections are the most common causes of mortality. There are many hypotheses about the pathogenesis of CF lung disease. CF’s relationship with lipids is not understood. Sphingomyelin (SM) and ceramide (C) are sphingolipid metabolites which play a role in many cellular events. Disorders in lipid metabolism have been linked to the pathogenesis of many diseases, but it has not been elucidated in which pathophysiological processes and how C and SM are involved. YKL-40 is a chitinase-like glycoprotein secreted from macrophages. It is physiological role is not known yet. It is thought to have been involved in chronic inflammation. Chitotriosidase can also be evaluated as an inflammatory protein because it is secreted from active macrophages. Plasma samples were obtained from whole blood collected from CF patients who were hospitalized with pulmonary exacerbation during exacerbation, discharge after antibiotic treatment and control within the first 3 months after discharge period. In these plasma samples, YKL-40 and chitotriosidase activities were measured in order to evaluate the level of inflammation. C and SM levels were measured in order to observe changes of sfingolipid metabolites during disease course. The results were compared to healthy individuals of similar age range. Except the 16 SM level of the control of the adult CF patient group; all plasma SM and C levels in exacerbation, discharge and control were significantly lower when compared to healthy controls (p<0.001 and p<0.05). For the children with CF in exacerbation 16 SM, 18 SM, 24 SM, C 22, C 24, in discharge 18 SM, 24 SM, C 18, C 20, C 22, C 24 and control period 18 SM, 24 SM, C 24 levels were significantly lower than healthy controls (p<0.001/p<0.05). YKL-40 levels of adult and pediatric CF patients were significantly higher than healthy controls at all periods (p<0.001/p<0.05). In addition, FVC and FEV1 values of pediatric patients (FVC: r:-0.70, p<0.05/FEV1: r:-0.72, p<0.05) and adult CF patients with FEV1≤50 (FVC: r:-0.64, p<0.05/FEV1: r:-0.64, p<0.05) in exacerbation period were found to correlate negatively with YKL-40 levels in the same period. The chitotriosidase activities of adult CF patients were significantly higher than healthy controls at all periods (p<0.001/p<0.05), the chitotriosidase activities of pediatric CF patients were not significantly different from healthy controls in any of the periods. C, SM and YKL-40 levels and chitotriosidase activities did not show any significant difference between the periods of the disease According to our data, it is clear that the sphingolipid metabolism changes as a result of the cystic fibrosis transmembrane conductance regulator (CFTR) mutation. It is known that CFTR disorder impairs vesical pH acidification and reduces the activity of acidic sphingomyelinase (Smase), which is active at acidic pH. For this reason, C and SM production may be restricted in CF patients. The glutathione (GSH) transporter is CFTR dependent. In CFTR mutant cell lines GSH levels are shown to be higher than normal cells. Another study showed that high levels of GSH inhibited C production in the lungs. High intracellular GSH concentrations in CF according to the literature may be leading to a decrease in C synthesis via Smase pathway. Significant differences in SM and C types compared to healthy controls are more pronounced in adult patients than children. This can be explained by the fact that adult patients are more exposed to the burden of chronic illness due to their older age, and thus their sphingolipid metabolism may be more affected. Chitotriosidase activity was significantly higher in all periods of adult patients than in healthy controls, but not significantly different in children compared to healthy controls. This suggests that chitotriosidase activity reflects chronic inflammation better in older patients. YKL-40 was found to be significantly higher in both adult and pediatric patients than healthy control in all three periods, and negative correlation with pulmonary function tests suggests that YKL-40 may be valuable in following pulmonary function in CF patients. C, SM and YKL-40 levels and chitotriosidase activities do not differ significantly between the periods of the disease suggests that the research should be done with more patients besides the result that would not be beneficial for the follow-up of the disease.