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- Bergemalm, Daniel, 1977-, et al.
(författare)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 2. |
- Ocklind, Anette
(författare)
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The prostanoid FP receptor and uveoscleral outflow : A study of FP receptor expression and functions in the eye
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostaglandin F2α is a prostanoid FP receptor agonist which acts as an intraocular pressure-lowering agent by increasing the uveoscleral outflow of aqueous humour through the ciliary muscle. The aim of this, thesis was to investigate possible mechanisms of the increased uveoscleral outflow induced by prostaglandin F2α and its analogue latanoprost acid.A cell line, suitable for biochemical isolation of the FP receptor, was established. Cat iris sphincter muscle cells were immortalised using SV-40 virus. The selected cell line was characterised morphologically, biochemically and pharmacologically.During the study, others reported the primary amino acid sequence deduced from cDNA cloning of ratcorpus luteum FP receptor. This FP receptor sequence was used to generate reagents that allowed studies of the distribution of the FP receptor in various rat organs and in the cynomolgus monkey eye by immunohistochemistry and in situ hybridisation. The FP receptor messenger RNA and protein were detected in several organs and tissue types of the rat, with the strongest expression in muscle and epithelial tissues. The FP receptor was also detected in the monkey eye, with the strongest expression in the ciliary muscle and epithelia.The effects of prostaglandin F2α and latanoprost acid on the extracellular matrix of the ciliary muscle were investigated in cultures of ciliary smooth muscle cells. Immunocytochemistry on the cells suggested that both prostaglandins reduced the deposition of extracellular matrix components such as collagens, fibronectin, laminin and hyaluronan. Furthermore, both prostaglandins increased cellular expression of matrix metalloproteinase types 2 and 3, as revealed by immunofluorescence and zymography, and stimulated the generation of plasmin. Immunohistochemistry on tissue sections of monkey eyes, obtained after in vivo treatment with latanoprost also suggested that the expression of collagens were reduced. Thus our results indicate that the extracellular matrix is remodelled by these prostaglandins, possibly by inducing matrix metalloproteinases.The adhesive interactions between cells and their extracellular matrix were also investigated. Cultured ciliary muscle cells were treated with latanoprost acid and then stained specifically for actin and vinculin which is present in focal adhesions. Effects on intracellular Ca2+ mobilization were studied fluorimetrically in cells loaded with the Ca2+ indicator fluo-3. Latanoprost acid induced transient rearrangements of actin filaments in the cell periphery, stimulated translocation of focal adhesions and increased intracellular Ca2+. Altogether, the data suggest that latanoprost induces a motility response in ciliary muscle cells. Such a motility response may be important for tissue compaction and thereby indirectly for the increased aqueous humour flow through the muscle. In summary, the results suggest that prostaglandin F2α and latanoprost increase uveoscleral outflow of aqueous humour by affecting the composition of the extracellular matrix and the cellular interaction with these components in the ciliary muscle. The FP receptor was abundantly expressed in the ciliary muscle. Since latanoprost is a selective FP receptor agonist, the effect is very likely mediated by the prostanoid FP receptor.
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