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PubMed2005

Molecular pathways of endothelial cell activation for (targeted) pharmacological intervention of chronic inflammatory diseases.

In chronic inflammatory conditions, endothelial cells actively recruit immune cells from the circulation into the underlying tissue and participate in angiogenesis to support the continuous demand for oxygen and nutrients. They do so in response to activation by cytokines and growth factors such as tumour necrosis factor alpha (TNFalpha), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF), and fibroblast growth factors (FGFs). Receptor triggering initiates intracellular signal transduction leading to activation of nuclear factor kappaB (NFkappaB), mitogen activated protein kinase (MAPK) activity, and nitric oxide and reactive oxygen species production, among others. As a result, adhesion molecules, cytokines and chemokines, and a variety of other genes are being expressed that mediate and control the inflammatory process. In recent years, different classes of drugs have been developed that interfere with selected enzymes involved in the intracellular signalling cascades. In endothelial cell cultures, they exert potent inhibitory effects on the expression of genes, while several studies also report on in vivo effectiveness to confine the inflammatory responses. To prevent undesired toxicity and to improve drug behaviour and efficacy, drug carrier systems have been developed that selectively deliver the therapeutics into the activated endothelial cells. The above subjects are recapitulated to give an overview on the status of development of endothelial cell directed therapeutic strategies to pharmacologically interfere with chronic inflammatory diseases.

Animals↗
PubMed2006

Selected players in the inflammation cascade and drugs that target these inflammation genes against metastasis.

Despite many recent advances the prognosis of cancer patients with metastasis still remains poor. In metastatic invasion, tumor cells interact with endothelial cells through several distinct adhesion molecules. Adherent tumor cells extravasate into tissues by degrading basement membranes with matrix degrading enzymes such as heparanases and matrix metalloproteinases. Endothelial expression of matrix degrading enzymes and adhesion molecules are under the control of inflammatory cytokines. These inflammatory proteins and the signaling pathways involved in the expression of these genes are under intense investigation as therapeutic targets to prevent tumor growth and metastasis. The current review focuses on selected players of the inflammation cascade and drugs that target these inflammatory genes.

Animals↗
PubMed2005

Nitric oxide and the resolution of inflammation: implications for atherosclerosis.

The ubiquitous free radical, nitric oxide (NO), plays an important role in many biological processes including the regulation of the inflammatory response. Alterations in NO synthesis by endogenous systems likely influence inflammatory processes occurring in a wide range of diseases including many in the cardiovascular system (e.g. atherosclerosis). Progression of inflammatory conditions depends not only upon the recruitment and activation of inflammatory cells but also upon their subsequent removal from the inflammatory milieu. Apoptosis, or programmed cell death, is a fundamental process regulating inflammatory cell survival and is critically involved in ensuring the successful resolution of an inflammatory response. Apoptosis results in shutdown of secretory pathways and renders effete, but potentially highly histotoxic, cells instantly recognisable for non-inflammatory clearance by phagocytes (e.g., macrophages). However, dysregulation of apoptosis and phagocytic clearance mechanisms can have drastic consequences for development and resolution of inflammatory processes. In this review we highlight the complexities of NO-mediated regulation of inflammatory cell apoptosis and clearance by phagocytes and discuss the molecular mechanisms controlling these NO mediated effects. We believe that manipulation of pathways involving NO may have previously unrecognised therapeutic potential for limiting or resolving inflammatory and cardiovascular disease.

Apoptosis↗
PubMed2021

RNA-seq Analysis of Peri-Implant Tissue Shows Differences in Immune, Notch, Wnt, and Angiogenesis Pathways in Aged Versus Young Mice.

The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch, and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

AGING↗
PubMed1999

CD47 ligation selectively downregulates human interleukin 12 production.

Interleukin (IL)-12 plays a key role not only in protective innate and adaptive T helper cell type 1 (Th1) responses but also in chronic inflammatory diseases. We report here that engagement of CD47 by either monoclonal antibody, its natural ligand thrombospondin (TSP), or 4N1K (a peptide of the COOH-terminal domain of TSP selectively binding CD47) inhibits IL-12 release by monocytes. The suppression occurred after T cell-dependent or -independent stimulation of monocytes and was selective for IL-12 inasmuch as the production of tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and granulocyte/macrophage colony-stimulating factor was not inhibited. CD47 ligation did not alter transforming growth factor (TGF)-beta and IL-10 production, and the suppressive effect on IL-12 was not due to autocrine secretion of TGF-beta or IL-10. The IL-12 inhibition was not mediated by Fcgamma receptor ligation, did not require extracellular Ca(2+) influx, but was reversed by two phosphoinositide 3-kinase inhibitors (wortmannin and Ly294002). Thus, engagement of CD47 on monocytes by TSP, which transiently accumulates at the inflammatory site, is a novel and unexplored pathway to selectively downregulate IL-12 response. The pathway may be relevant in limiting the duration and intensity of the inflammatory response, and in developing novel therapeutic strategies for Th1-mediated diseases.

Androstadienes↗
PubMed1998

Mechanisms of immune cell-mediated tissue injury in inflammatory bowel disease (Review).

This review discusses the mechanisms and pathways of immune cell-mediated intestinal inflammation and tissue injury in inflammatory bowel disease (IBD). Our lack of understanding of how the mucosal immune system normally functions to maintain the balance between tolerance and immunity to innumerable dietary and bacterial constituents of the gut is perhaps the biggest obstacle to understanding the cause(s) of IBD, and to developing more effective treatments for these debilitating disorders. Evidence that abnormalities or disruptions in the interaction of immune cells and gut bacteria can trigger or contribute to changes in the composition, regulation and activity of the mucosal immune system that result in inflammatory immune responses and tissue injury are discussed. Based upon these studies, we propose a model to explain how a breakdown in regulation and failure to resolve immune responses in the gut mucosa results in persistent activation of T lymphocytes and other immune cells and the uncontrolled production of soluble inflammatory mediators that directly or indirectly produce the pathophysiological changes and tissue injury characteristic of IBD.

Animals↗
PubMed2005

The regulation of the expression of inducible nitric oxide synthase by Src-family tyrosine kinases mediated through MyD88-independent signaling pathways of Toll-like receptor 4.

Bacterial lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4) leading to the expression of inflammatory gene products. Src-family tyrosine kinases (STKs) are known to be activated by LPS in monocytes/macrophages. Therefore, we determined the role of STKs in TLR4 signaling pathways and target gene expression in macrophages. The activation of NFkappaB, and p38 MAPK, and the expression of inducible nitric oxide synthase (iNOS) induced by LPS were not affected in macrophages deficient in three STKs (Lyn, Hck, and Fgr). These results suggest that the deletion of the three STKs among possibly nine STKs is not sufficient to abolish total activity of STKs possibly due to the functional redundancy of other STKs present in macrophages. However, two structurally unrelated pan-inhibitors of STKs, PP1 and SU6656, suppressed LPS-induced iNOS expression in MyD88-knockout as well as wild-type macrophages. The suppression of iNOS expression by the inhibitors was correlated with the downregulation of IFNbeta (a MyD88-independent gene) expression and subsequent decrease in STAT1 phosphorylation. Moreover, PP1 suppressed the expression of IFNbeta and iNOS induced by TRIF, a MyD88-independent adaptor of TLR4. PP1 suppressed STAT1 phosphorylation induced by LPS, but not by IFNbeta suggesting that STKs are involved in the primary downstream signaling pathways of TLR4, but not the secondary signaling pathways downstream of IFNbeta receptor. Together, these results demonstrate that STKs play a positive regulatory role in TLR4-mediated iNOS expression in a MyD88-independent (TRIF-dependent) manner. These results provide new insight in understanding the role of STKs in TLR4 signaling pathways and inflammatory target gene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology.

Tumor necrosis factor-alpha (TNF) is one member of a large family of inflammatory cytokines that share common signal pathways, including activation of the transcription factor nuclear factor kappa B (Nf-kappa B) and stimulation of the apoptotic pathway. Data derived from early work supported a role for TNF as a skeletal catabolic agent that stimulates osteoclastogenesis while simultaneously inhibiting osteoblast function. The finding that estrogen deficiency was associated with increased production of cytokines led to a barrage of studies and lively debate on the relative contributions of TNF and other cytokines on bone loss, on the potential cell sources of TNF in the bone microenvironment, and on the mechanism of TNF action. TNF has a central role in bone pathophysiology. TNF is necessary for stimulation of osteoclastogenesis along with the receptor activator of Nf-kappa B ligand (RANKL). TNF also stimulates osteoblasts in a manner that hinders their bone-formative action. TNF suppresses recruitment of osteoblasts from progenitor cells, inhibits the expression of matrix protein genes, and stimulates expression of genes that amplify osteoclastogenesis. TNF may also affect skeletal metabolism by inducing resistance to 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) by a mechanism that extends to other members of the steroid hormone nuclear receptor family. Thus, TNF assails bone at many levels. This review will focus on the cellular and molecular mechanisms of TNF action in the skeleton that result in increased bone resorption and impaired formation. TNF and its signal pathway remains an important target for the development of new therapies for bone loss from osteoporosis and inflammatory arthritis.

Animals↗
PubMed2003

MAPK regulation of gene expression in airway smooth muscle.

Mitogen-activated protein kinases (MAPK) are important components of signaling modules activated by neurotransmitters, cytokines, and growth factors, as well as chemical and mechanical stressors. In the airway, these external signals produce acute responses that modify smooth muscle contraction and may also induce chronic responses that modify airway structure. Both acute and chronic events in airway remodeling result from altered expression of multiple genes encoding protein mediators of cell-cell signaling, extracellular matrix remodeling, cell cycle control and intracellular signaling pathways. This review will focus on inflammatory and growth factor mediators of cell-cell signaling regulated by the ERK and p38 MAPK pathways in airway smooth muscle (ASM). These signaling mediators affect ASM tissue mechanics, cell migration, and gene expression patterns in a paracrine and autocrine fashion, although the relative importance of each MAPK pathway varies with the stimulus. These events thereby contribute to normal airway function and participate in pathological changes in ASM that accompany symptoms of asthma.

Animals↗
PubMed2003

Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors.

Differentiated thyroid carcinomas are the most frequent endocrine neoplasms, but account for few cancer-related deaths. Although the indolent growth of these cancers correlates well with longevity, the biological basis for this good prognosis is not known. In contrast, two of the most frequent autoimmune diseases involve the thyroid suggesting a high propensity for this organ to invoke destructive immunity. Unfortunately, the mechanism linking malignancy and autoimmunity is not clear, although the expression of the oncogenic fusion protein RET/PTC3 (RP3) in both of these disorders may provide a clue. Interestingly, the signaling caused by activated RET kinase involves overlapping pathways and some common to the inflammatory response. Accordingly, we analyzed the function of RP3 and a mutant RP3 molecule to induce proinflammatory pathways in thyroid epithelial cells. Indeed, we find that RP3 alone causes increases in nuclear NF-kappaB activity and secretion of MCP-1 and GM-CSF. Finally, transfer of RP3-expressing thyrocytes into mice in vivo attracted dense macrophage infiltrates, which lead to rapid thyroid cell death. Further, cytokine synthesis and inflammation was largely abrogated by mutation of RP3 Tyr588; an important protein-binding site for downstream signaling. Together, these studies implicate oncogene-induced cytokine-signaling pathways in a new mechanism linking inflammation with cancer.

Animals↗
PubMed1980

Petrolatum: interference with the oxidation of arachidonic acid.

Microsomal preparations from petrolatum-treated wound skin contained significantly less arachidonic acid-dependent oxidative capacity when compared to activities in untreated wounded skin (t = 6.06, P < 0.001). Microsomes from both untreated and petrolatum-treated wounded skin produced similar quantities of PGE2 and PGF2 alpha; however, microsomal lipoxygenase activity in petrolatum-treated wounded skin was depressed when compared to that in untreated wounded skin. Microsomal preparations from normal pig skin treated with petrolatum oxidized arachidonic acid at a similar rate to those from untreated control skin. Increasing quantities of petrolatum progressively inhibited the synthesis of PGE2 and PGF2 alpha by fetal calf skin microsomes in vitro as determined by both the oxidation of arachidonic acid and the quantification of radioactive product. Topical application of banal compounds that contain lipid substances may therefore alter the cutaneous inflammatory response by local suppression of pathways that generate hydroxy-fatty acids, substances that are known to be chemotactic and pro-inflammatory.

Animals↗
PubMed2003

Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes.

Pancreatic islet beta-cell death occurs in type 1 and 2 diabetes mellitus, leading to absolute or relative insulin deficiency. beta-cell death in type 1 diabetes is due predominantly to autoimmunity. In type 2 diabetes beta-cell death occurs as the combined consequence of increased circulating glucose and saturated fatty acids together with adipocyte secreted factors and chronic activation of the innate immune system. In both diabetes types intra-islet inflammatory mediators seem to trigger a final common pathway leading to beta-cell apoptosis. Therefore anti-inflammatory therapeutic approaches designed to block beta-cell apoptosis could be a significant new development in type 1 and 2 diabetes.

Adipocytes↗
PubMed2001

Regulation of inflammatory responses by natural anticoagulants.

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) are critically involved in activation of the coagulation system in sepsis, leading to disseminated intravascular coagulation (DIC). Natural anticoagulants such as antithrombin (AT) and activated protein C (APC) regulate the coagulation system by inhibiting thrombin generation. In addition to these anticoagulant effects, both AT and APC have been shown to attenuate inflammatory responses induced by various noxious stimuli in rats such as lipopolysaccharide (LPS) challenge. AT promotes the endothelial release of prostacyclin, a potent anti-inflammatory prostaglandin that inhibits the monocytic production of TNF-alpha, by interacting with cell-surface heparin-like substances. APC directly inhibits the production of TNF-alpha by inhibiting the activation of both nudear factor kappaB (NFkappaB) and activator protein-1 in monocytes stimulated with LPS. Thrombomodulin, an endothelial membranous integral protein that binds thrombin, exerts anti-inflammatory effects by generating APC. Furthermore, tissue factor pathway inhibitor, a natural anticoagulant for the extrinsic pathway of the coagulation system, also attenuates LPS-induced inflammatory responses in rats by inhibiting TNF-alpha production by monocytes. These findings strongly suggest that natural anticoagulants could regulate inflammatory responses as well as the coagulation system in rats by inhibiting the monocytic production of TNF-alpha. Such anti-inflammatory properties of natural anticoagulants are potentially important for their replacement in patients with sepsis who frequently develop DIC and organ failure as inflammatory responses.

Animals↗
PubMed2006

Increased thalamic neurodegeneration following ischaemic cortical stroke in osteopontin-deficient mice.

Inflammation aggravates brain injury caused by stroke and neurodegeneration. Osteopontin (OPN) is a cytokine-like glycoprotein that binds to various integrins and CD44 variants. OPN exerts proinflammatory effects in autoimmune conditions but also has cytoprotective properties and participates in wound healing. In this study, we addressed the role of OPN in ischaemic brain injury using OPN knock-out (KO) mice in models of cortical stroke. Compared with wild-type animals, OPN KO mice exhibited unaltered infarct development at the primary injury site but greatly increased retrograde degeneration of the ipsilateral thalamus. Thalamic neurodegeneration in OPN-deficient mice was associated with pronounced microglia activation and inflammatory gene expression and could be attenuated via pharmacological blockade of the inducible nitric oxide synthase (iNOS). Therefore, delayed neurodegeneration in OPN-deficient mice was at least partly due to an excessive release of nitric oxide via the iNOS pathway. Neuroprotective and anti-inflammatory effects of OPN may be relevant for a variety of neurological disease conditions.

Animals↗
PubMed2004

Pancreatic proteases and inflammatory mediators in peritoneal fluid during splanchnic arterial occlusion and reperfusion.

Pancreatic enzymes in the ischemic intestine are involved in the production of in vivo inflammatory mediators. These mediators stimulate cells in the cardiovascular system during shock and initiate multiorgan failure. An important aspect that controls the extent of the inflammation is the dispersion of these mediators from the ischemic intestine. In the past, two pathways for dispersion of these inflammatory mediators have been identified, absorption into the intestinal venous circulation and uptake into the lymphatics. We hypothesize here that the inflammatory mediators produced by pancreatic digestive enzymes in the lumen of the intestine may also be released directly into the peritoneal space. To assess the presence of inflammatory mediators in the peritoneal cavity in response to splanchnic arterial occlusion (90 min) and reperfusion (SAO shock), we measured the ability of fluid collected from this cavity to activate naive donor granulocytes. After SAO in control rats, peritoneal lavage fluid caused activation of naive donor granulocytes when tested in vitro. In contrast, when the lumen of the small intestine was flushed with a broad-acting pancreatic enzyme inhibitor (6-amidino-2-naphtyl p-guanidinobenzoate dimethanesulfate), the fluid no longer caused leukocyte activation. Reduction of the levels of inflammatory mediators in the peritoneal fluid was associated with an attenuation in the fall of blood pressure after SAO shock. These results indicate that the inflammatory mediators, which are produced by pancreatic digestive enzymes, can be absorbed directly into the systemic circulation via a transperitoneal route and play a part in the development of multiorgan failure.

Animals↗
PubMed2005

A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense.

The surface of the eye actively suppresses inflammation while maintaining a remarkable capacity for epithelial wound repair. Our understanding of mechanisms that balance inflammatory/reparative responses to provide effective host defense while preserving tissue function is limited, in particular, in the cornea. Lipoxin A(4) (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15-lipoxygenase (LOX) pathways that exhibit anti-inflammatory and neuroprotective properties. Here, we demonstrate that mouse corneas generate endogenous LXA(4) and NPD1. 12/15-LOX (Alox15) and LXA(4) receptor mRNA expression as well as LXA(4) formation were abrogated by epithelial removal and restored during wound healing. Amplification of these pathways by topical treatment with LXA(4) or NPD1 (1 microg) increased the rate of re-epithelialization (65-90%, n = 6-10, p < 0.03) and attenuated the sequelae of thermal injury. In contrast, the proinflammatory eicosanoids, LTB(4) and 12R-hydroxyeicosatrienoic acid, had no impact on corneal re-epithelialization. Epithelial removal induced a temporally defined influx of neutrophils into the stroma as well as formation of the proinflammatory chemokine KC. Topical treatment with LXA(4) and NPD1 significantly increased PMNs in the cornea while abrogating KC formation by 60%. More importantly, Alox15-deficient mice exhibited a defect in both corneal re-epithelialization and neutrophil recruitment that correlated with a 43% reduction in endogenous LXA(4) formation. Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA(4) and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties.

Animals↗
PubMed2006

Bile acids and cytokines inhibit the human cholesterol 7 alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells.

Cholesterol 7 alpha-hydroxylase (CYP7A1) of the bile acid biosynthesis pathway is suppressed by bile acids and inflammatory cytokines. Bile acids are known to induce inflammatory cytokines to activate the mitogen-activated protein kinase/c-Jun N-terminal kinase (JNK) signaling pathway that inhibits CYP7A1 gene transcription. c-Jun has been postulated to mediate bile acid inhibition of CYP7A1. However, the c-Jun target involved in the regulation of CYP7A1 is unknown. Human primary hepatocytes and HepG2 cells were used as models to study chenodeoxycholic acid (CDCA) and interleukin-1 beta (IL-1 beta) regulation of human CYP7A1 gene expression via real-time polymerase chain reaction, reporter assays, co-immunoprecipitation and chromatin immunocipitation (ChIP) assays. IL-1 beta and CDCA reduced CYP7A1 but induced c-Jun messenger RNA expression in human primary hepatocytes. IL-1beta inhibited human CYP7A1 reporter activity via the HNF4 alpha binding site. A JNK-specific inhibitor blocked the inhibitory effect of IL-1 beta on HNF4 alpha expression and CYP7A1 reporter activity. c-Jun inhibited HNF4 alpha and PPARgamma coactivator-1 alpha (PGC-1 alpha) coactivation of CYP7A1 reporter activity, whereas a dominant negative c-Jun did not. Co-immunoprecipitation and ChIP assays revealed that IL-1 beta and CDCA reduced HNF4 alpha bound to the CYP7A1 chromatin, and that c-Jun interacted with HNF4 alpha and blocked HNF4 alpha recruitment of PGC-1 alpha to the CYP7A1 chromatin. In conclusion, IL-1 beta and CDCA inhibit HNF4 alpha but induce c-Jun, which in turn blocks HNF 4 alpha recruitment of PGC-1 alpha to the CYP7A1 chromatin and results in inhibition of CYP7A1 gene transcription. The JNK/c-Jun signaling pathway inhibits bile acid synthesis and protects hepatocytes against the toxic effect of inflammatory agents.

Bile Acids and Salts↗
PubMed2026

Metabolomic Signatures of Inflammation in Chronic Kidney Disease.

RATIONALE & OBJECTIVE: Inflammation is associated with adverse kidney, cardiovascular, and mortality outcomes. Investigation of the metabolic milieu as it relates to inflammation may provide important insights into these disease processes. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: African American Study of Kidney Disease and Hypertension (AASK), Atherosclerosis Risk in Communities (ARIC) study, and Boston Kidney Biopsy Cohort (BKBC) participants with available metabolomics and inflammatory protein data. PREDICTORS: Baseline blood levels of 718 metabolites. OUTCOMES: Baseline and longitudinal changes in blood levels of tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), tumor necrosis factor-alpha (TNF-&#x3b1;), interferon-gamma (IFN-&#x3b3;), interleukins 6, 8, and 10 (IL-6, IL-8, IL-10), uromodulin (UMOD), and epidermal growth factor (EGF). ANALYTICAL APPROACH: Multivariable linear regression and linear mixed-effects models. RESULTS: Among 491 AASK participants (mean age 54 years; 37% women; mean glomerular filtration rate, 45 mL/min/1.73 m2), 367 cross-sectional associations between metabolites and inflammatory proteins were significant after correction for multiple comparisons. The direction of association was mostly positive for TNFR1 (97%), TNFR2 (97%), IL-8 (77%), and IL-10 (100%); negative for UMOD (80%) and EGF (97%); and variable for TNF-&#x237a;, IFN-&#x3b3;, and IL-6. Pathways were distinct for several inflammatory proteins (eg, tryptophan metabolism for TNFR2). Forty-five associations between metabolites and longitudinal change in inflammatory proteins were identified. Notable metabolites included tigylcarnitine and N 2,N 5-diacetylornithine, which were associated with 2-year increases in TNFR1 and/or TNFR2, and 1,5-anhydroglucitol, where lower levels were associated with decreases in UMOD. In ARIC (n = 3,773) and BKBC (n = 413), replication of cross-sectional associations was excellent for TNFR1 (ARIC 83%; BKBC 85%) and TNFR2 (ARIC 64%; BKBC 79%) but poor for IL-8 (ARIC 3%; BKBC 3%). LIMITATIONS: Metabolite data limited to baseline visit; potential for residual confounding. CONCLUSIONS: Using an untargeted approach, multiple metabolites were cross-sectionally and longitudinally associated with inflammatory proteins in persons with chronic kidney disease.

Chronic kidney disease↗