The effects of TNF-alpha blocker and IL-6 blocker therapy on vascular function in a collagen induced arthritis rat model

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dc.contributor.authorFourie, Serena
dc.date.accessioned2020-11-07T16:26:22Z
dc.date.available2020-11-07T16:26:22Z
dc.date.issued2020
dc.descriptionA dissertation submitted in fulfilment of the requirements for the degree of Master of Science in Medicine to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2020en_ZA
dc.description.abstractEndothelial dysfunction and arterial stiffness are associated with increased cardiovascular morbidity and mortality in rheumatoid arthritis (RA). Chronic systemic inflammation appears to play a vital role in the development of endothelial dysfunction and arterial stiffness in patients with RA. Although biologic disease modifying antirheumatic drugs (DMARDS), including tumour necrosis factor alpha (TNF-α) blockers and interleukin-6 (IL-6) blockers have shown reduced inflammatory status and disease progression in RA patients, their effect on cardiovascular disease risk is inconsistent. The role of biologic DMARDS on endothelial function and arterial stiffness in the collagen induced arthritis (CIA) rat model, has not been investigated. Male (n=47) and female (n=31) Sprague-Dawley rats were randomly divided into the control (n=22), inflammation (n=26), tumor necrosis factor-alpha blocker (TNF-α blocker; n=15) and interleukin-6 blocker (IL-6 blocker; n=15) groups. To induce arthritis, rats in the inflammation, TNF-α blocker and IL-6 blocker groups received a 0.2 ml subcutaneous injection of bovine type-II collagen emulsified in incomplete Freund’s adjuvant at the base of the tail. Following the onset of inflammation, the TNF-α blocker group received 10mg/kg intraperitoneal injections of Etanercept (TNF-α receptor blocker) every three days for six weeks and the IL-6 blocker group received 8mg/kg intraperitoneal injections of Tocilizumab (IL-6 receptor blocker) once a week for 6 weeks. The control group received a 0.2 ml injection of saline at the base of the tail. Body weight, food intake, blood pressure, arthritis scores and paw thickness measurements at the tarsometatarsal and ankle joints were assessed every two weeks. After six weeks of treatment, arterial stiffness and vascular reactivity in mesenteric and renal arteries were assessed using the pulse pen and wire-myograph, respectively. Serum concentrations of TNF-α, IL-6 and C-reactive protein (CRP) were measured by ELISA. Group differences in all arthritis scores were measured by repeated measures analysis of variance (ANOVA). Group iv differences in inflammatory and vascular function markers were assessed using a two-way ANOVA with a Tukey post-hoc test. Associations between inflammatory markers and vascular reactivity changes were determined by Pearson’s correlations. There were no significant differences in body weight, food intake and blood pressure between the groups at baseline and at termination (all p>0.05). Arthritis scores and paw thickness measurements were significantly increased in the inflammation, TNF-α blocker and IL-6 blocker groups compared to the control group at termination (all p<0.01). There were no differences in arthritis scores or paw thickness measurements between the inflammation, TNF α blocker and IL-6 blocker groups (p<0.05). Circulating TNF-α concentrations were significantly higher in the inflammation, TNF-α blocker and IL-6 blocker groups compared to the control group (p<0.0001, p=0.02, p=0.001 respectively). There were no differences in the contractile responses in mesenteric or renal arteries between any of the groups (all p>0.05). Acetylcholine-induced relaxation in mesenteric (p<0.0001) and renal arteries (p<0.0001) was significantly impaired in the inflammation compared to control group. In the IL-6 blocker group, ACh-induced relaxation in both mesenteric (p<0.0001) and renal arteries (p<0.0001) were significantly greater compared to the inflammation group. There were no differences in ACh-induced relaxation between the inflammation and TNF-α blocker groups in either renal or mesenteric arteries (all p>0.05). Markers of arterial stiffness were not different between the groups (all p>0.05). Greater serum concentrations of TNF-α (r=-0.36, p=0.01), IL-6 (r=-0.30, p=0.02) and CRP (r=-0.34, p=0.01) were associated with impaired KCl-induced contractions (lower Emax) in mesenteric arteries. Greater serum concentrations of TNF-α (r=-0.68, p<0.0001), IL-6 (r=-0.54, p=0.001) and CRP (r=-0.68, p<0.0001) were associated with impaired ACh-induced relaxation (lower Emax) in renal arteries. In conclusion, chronic high-grade inflammation impairs vascular relaxation, but not contraction, in resistance and large arteries. Despite unchanged circulating inflammatory v marker concentrations, IL-6 blocker treatment reduced the inflammation-induced impairments in endothelial function in resistance and large arteries. However, the mechanisms underlying the improved vascular function requires further investigation.en_ZA
dc.description.librarianTL (2020)en_ZA
dc.facultyFaculty of Health Sciencesen_ZA
dc.identifier.urihttps://hdl.handle.net/10539/29995
dc.language.isoenen_ZA
dc.schoolSchool of Physiologyen_ZA
dc.titleThe effects of TNF-alpha blocker and IL-6 blocker therapy on vascular function in a collagen induced arthritis rat modelen_ZA
dc.typeThesisen_ZA
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