Dynamics of inflammatory markers in patients with normal and impaired glucose metabolism during lung exacerbation treatment

Cystic fibrosis (CF) is one of the most common autosomal-recessive inherited diseases. The primary genetic defect in CF is aligned CFTR gene mutation which encodes a membrane protein functioning as cAMP-depended chloride channel. Classic phenotypical manifestations of CF include chronic obstructive pulmonary disease with bronchiectasis, persisting infection (St. aureus, Ps. aeruginosa, B. cepacia) and aberrant inflammatory response, as well as exocrine pancreatic insufficiency with malabsorption, hypotrophy and growth retardation. CFTR deficiency is also accompanied by β-cell pancreatic dysfunction, causing glucose metabolism disturbances and CF-related diabetes. The aim of the study was the comparison of inflammatory markers dynamics in patients with normal and disturbed glucose metabolism during pulmonary exacerbation treatment. The study included 10 patients with impaired glucose tolerance (Group 1) and 24 patients with normal carbohydrate metabolism (Group 2). Patients of the two groups did not significantly differ in demographic characteristics, pulmonary function test and body mass index parameters, as well as in the number of F508del mutation carriers and in the number of those who were infected with Ps. aeruginosa and B. cepacia complex. Blood sampling was performed twice: before and after a routine course of antibiotic therapy. Plasma levels of biomarkers including the antibodies to single- and double-stranded DNA (ss-DNA-IgG, ds-DNA-IgG, respectively), the hormones (dehydroepiandrosterone (DHEA) and DHEA sulfate), C-reactive protein (CRP), Mn-dependent superoxide dismutase (Mn-SOD), and the cytokines (tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), IFNα, tissue growth factor-β1 (TGF-β1), interleukin-4 (IL-4), IL-6, IL-10, IL-17A) were assessed using commercial immunoassay kits. Our study shows that antibiotic treatment did not have a sufficient influence on levels of inflammatory markers in patients with disturbances of glucose metabolism while patients with normal glucose tolerance demonstrated a significant reduction in inflammatory marker values after the therapy. The data may suggest both impaired effectivity of antibiotic treatment and aberrant inflammatory response in patients with glucose intolerance.

1. Bell S.C., Mall M.A., Gutierrez H., Macek M., Madge S., Davies J.C., Burgel P.R., Tullis E., Castaños C., Castellani C., Byrnes C.A., Cathcart F., Chotirmall S.H., Cosgriff R., Eichler I., Fajac I., Goss C.H., Drevinek P., Farrell P.M., Gravelle A.M., Havermans T., Mayer-Hamblett N., Kashirskaya N., Kerem E., Mathew J.L., McKone E.F., Naehrlich L., Nasr S.Z., Oates G.R., O’Neill C., Pypops U., Raraigh K.S., Rowe S.M., Southern K.W., Sivam S., Stephenson A.L., Zampoli M., Ratjen F. The future of cystic fibrosis care: a global perspective. Lancet Respir. Med., 2020, Vol. 8, no. 1, pp. 65-124.

2. Birket S.E., Chu K.K., Liu L., Houser G.H., Diephuis B.J., Wilsterman E.J., Dierksen G., Mazur M., Shastry S., Li Y., Watson J.D., Smith A.T., Schuster B.S., Hanes J., Grizzle W.E., Sorscher E.J., Tearney G.J., Rowe S.M. A functional anatomic defect of the cystic fibrosis airway. Am. J. Respir. Crit. Care Med., 2014, Vol. 190, no. 4, pp. 421-432.

3. Costa M., Potvin S., Berthiaume Y., Gauthier L., Jeanneret A., Lavoie A., Levesque R., Chiasson J., Rabasa-Lhoret R. Diabetes: a major co-morbidity of cystic fibrosis. Diabetes Metab., 2005, Vol. 31, no. 3, Pt 1, pp. 221-232.

4. Edlund A., Esguerra J.L., Wendt A., Flodström-Tullberg M., Eliasson L. CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells. BMC Med., 2014, Vol. 12, 87. doi: 10.1186/1741-7015-12-87.

5. Hart N.J., Aramandla R., Poffenberger G., Fayolle C., Thames A.H., Bautista A., Spigelman A.F., Babon J.A.B., deNicola M.E., Dadi P.K., Bush W.S., Balamurugan A.N., Brissova M., Dai C., Prasad N., Bottino R., Jacobson D.A., Drumm M.L., Kent S.C., MacDonald P.E., Powers A.C. Cystic fibrosis-related diabetes is caused by islet loss and inflammation. JCI Insight, 2018, Vol. 3, no. 8, e98240. doi: 10.1172/jci.insight.98240.

6. Khan D., Kelsey R., Maheshwari R.R., Stone V.M., Hasib A., Manderson Koivula F.N., Watson A., Harkin S., Irwin N., Shaw J.A., McClenaghan N.H., Venglovecz V., Ébert A., Flodström-Tullberg M., White M.G., Kelly C. Short-term CFTR inhibition reduces islet area in C57BL/6 mice. Sci. Rep., 2019, Vol. 9, no. 1, 11244. doi: 10.1038/s41598-019-47745-w.

7. Koivula F.N.M., McClenaghan N.H., Harper A.G.S., Kelly C. Islet-intrinsic effects of CFTR mutation. Diabetologia, 2016, Vol. 59, no. 7, pp. 1350-1355.

8. Prentice B.J., Potter K.J., Coriati A., Boudreau V., Rusnell L., Kherani T., Senior P.A., Hameed S., Rabasa-Lhoret R. Cystic fibrosis-related diabetes: Clinical approach and knowledge gaps. Paediatr. Respir. Rev., 2023, Vol. 46, pp. 3-11.

9. Ren L.L., Li X.J., Duan T.T., Li Z.H., Yang J.Z., Zhang Y.M., Zou L., Miao H., Zhao Y.Y. Transforming growth factor-β signaling: From tissue fibrosis to therapeutic opportunities. Chem. Biol. Interact., 2023, Vol. 369, 110289. doi: 10.1016/j.cbi.2022.110289.

10. Saint-Criq V., Gray M.A. Role of CFTR in epithelial physiology. Cell. Mol. Life Sci., 2017, Vol. 74, no. 1, pp. 93-115.

11. Smerieri A., Montanini L., Maiuri L., Bernasconi S., Street M.E. FOXO1 content is reduced in cystic fibrosis and increases with IGF-I treatment. Int. J. Mol. Sci., 2014, Vol. 15, no. 10, pp. 18000-18022.

12. Smyth A.R., Bell S.C., Bojcin S., Bryon M., Duff A., Flume P., Kashirskaya N., Munck A., Ratjen F., Schwarzenberg S.J., Sermet-Gaudelus I., Southern K.W., Taccetti G., Ullrich G., Wolfe S.; European Cystic Fibrosis Society. European Cystic Fibrosis Society Standards of Care: Best Practice guidelines. J. Cyst. Fibros., 2014, Vol. 13, Suppl. 1, pp. S23-S42.

13. Tang X.X., Ostedgaard L.S., Hoegger M.J., Moninger T.O., Karp P.H., McMenimen J.D., Choudhury B., Varki A., Stoltz D.A., Welsh M.J. Acidic pH increases airway surface liquid viscosity in cystic fibrosis. J. Clin. Invest., 2016, Vol. 126, no. 3, pp. 879-891.