Inhaled fluticasone propionate reduces concentration of Mycoplasma pneumoniae, inflammation, and bronchial hyperresponsiveness in lungs of mice

BACKGROUND: Mycoplasma pneumoniae has been shown to induce airway inflammation and bronchial hyperresponsiveness (BHR) in mice. Inhaled corticosteroids are the mainstay of asthma treatment, but their effects on M. pneumoniae and associated airway inflammation and BHR are poorly understood. METHODS: Four groups of mice were studied to determine whether inhaled fluticasone propionate (FP) could attenuate airway inflammation and BHR by reducing or eliminating M. pneumoniae in lungs. The active group received aerosolized FP once daily for 5 days. Control mice received aerosolized sham solution plus M. pneumoniae, sham solution alone, or FP alone. RESULTS: Mice treated with sham solution or FP alone did not develop airway inflammation or BHR. Mice infected with M. pneumoniae (no FP) developed significant lung inflammation and BHR. FP treatment of infected mice reduced neutrophils in bronchoalveolar lavage fluid (BALF), lung inflammation, and BHR. Expression of Toll-like receptor 2 in lung tissue tended to be down-regulated (P=.18) by FP in infected mice. FP reduced M. pneumoniae by up to 20-fold in lung tissue but not in BALF. CONCLUSION: Inhaled FP suppresses airway inflammation and BHR, which may be caused, in part, by its ability to reduce concentrations of M. pneumoniae in lung tissue.     

Intestinal, adipose, and liver inflammation in diet-induced obese mice

Chronic inflammation and increased visceral adipose tissue (VAT) are key elements of the metabolic syndrome. Both are considered to play a pathogenic role in the development of liver steatosis and insulin resistance. The aim of the present study was to investigate the hypothesis that an inflamed intestine, induced both by diet and chemical irritation, could induce persistent inflammation in VAT. Female C57BL/6JOlaHsd mice were used. In study I, groups of mice (n = 6 per group) were given an obesity-inducing cafeteria diet (diet-induced obesity) or regular chow only (control) for 14 weeks. In study II, colitis in mice (n = 8) was induced by 3% dextran sulfate sodium in tap water for 5 days followed by 21 days of tap water alone. Healthy control mice (n = 8) had tap water only. At the end of the studies, all mice were killed; and blood and tissues were sampled and processed for analysis. Body weight of diet-induced obese mice was greatly increased, with evidence of systemic inflammation, insulin resistance, and liver steatosis. Tissue inflammation indexed by proinflammatory cytokine expression was recorded in liver, mesenteric fat, and proximal colon/distal ileum, but not in subcutaneous or perigonadal fat. In dextran sulfate sodium-induced colitis mice, mesenteric fat was even more inflamed than the colon, whereas a much milder inflammation was seen in liver and subcutaneous fat. The studies showed both diet- and colitis-initiated inflammation in mesenteric fat. Fat depots contiguous with intestine and their capacity for exaggerated inflammatory responses to conditions of impaired gut barrier function may account for the particularly pathogenic role of VAT in obesity-induced metabolic disorders.     

Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices

OBJECTIVES: The aim of this study was to compare the performance of fecal lactoferrin (Lf), calprotectin (Cal), polymorphonuclear neutrophil elastase (PMN-e), as well as serum C-reactive protein (CRP) in patients with inflammatory bowel diseases (IBD) to address (a) whether these markers can differentiate IBD patients with endoscopically assessed inflammation from IBD patients without inflammation and from irritable bowel syndrome (IBS); (b) whether they correlate with endoscopic severity of inflammation; and (c) whether a combination of fecal markers with the respective disease-specific activity indices may increase the diagnostic accuracy with reference to the endoscopic severity of inflammation. METHODS: Fecal levels of Lf, Cal, and PMN-e and serum CRP were assessed in 139 patients undergoing diagnostic ileocolonoscopy (54 IBS patients, 42 ulcerative colitis [UC], 43 Crohn's disease [CD]). Disease activity was determined for CU with the colitis activity index (CAI) and for CD with the Crohn's disease activity index (CDAI). The performance of each marker with reference to endoscopic inflammatory activity was assessed by computing correlations, and sensitivity and specificity using published as well as adjusted cutoffs. A comprehensive activity index was computed by combining results from fecal markers, serum CRP, and a clinical activity index. RESULTS: UC or CD patients with active inflammation demonstrated significantly higher levels of Lf, Cal, and PMN-e in feces as well as serum-CRP when compared to patients with inactive inflammation as well as patients with IBS (all P < 0.05). Using adjusted cutoffs enabled a marked improvement of all markers with an overall diagnostic accuracy in IBD of 80.0% for Lf, 80.0% for Cal, 74.1% for PMN-e, 64.0% for CRP, and 79.0% for the respective clinical disease scores. Cal showed the highest diagnostic accuracy in CD (81.4%), whereas Lf was superior to the other markers in UC (83.3%). The comprehensive activity index yielded a further improvement of sensitivity and specificity, with a diagnostic accuracy of 95.3% for UC patients. CONCLUSION: The fecal markers Lf, Cal, and PMN-e are able to differentiate active IBD from inactive IBD as well as from IBS. None of these three stool markers is consistently superior in its ability to reflect endoscopic inflammation, but all three are superior to CRP in their diagnostic accuracy. A combination of the stool markers with the CRP and a disease-specific activity index in a categorical comprehensive activity index can increase the diagnostic accuracy with reference to the endoscopic inflammation in UC.     

Obesity, inflammation, and insulin resistance

Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus.     

Inflammation, aging, and cancer vaccines

Immunosenescence is characterized by a series of changes of immune pathways, including a chronic state of low-grade inflammation. Mounting evidence from experimental and clinical studies suggests that persistent inflammation increases the risk of cancer and the progression of the disease. Cancer vaccination, which came into view in the last years as the most intriguing means of activating an immune response capable of effectively hampering the progression of the preclinical stages of a tumour, has been shown to be less effective in older age than in young adults. Available evidence on the use of inhibitors of inflammation has indicated their potential enhancement of cancer vaccines, suggesting the possibility to improve the low effectiveness of cancer vaccines in old age employing pharmacological or natural compounds-based anti-inflammatory intervention. This review addresses the effects of age and inflammation on cancer development and progression, and speculates as to whether the modulation of inflammation may influence the response to cancer immunization.     

Markers of inflammation in sarcoidosis: blood, urine, BAL, sputum, and exhaled gas

Sarcoidosis is characterized by intense inflammation at the different sites of localization. Many different mediators, such as cytokines, chemokines, and other proteins with various functions, that participate in its complex pathogenesis have been proposed as markers of inflammation. This article examines the principal literature on these different markers analyzed in serum, bronchoalveolar lavage, expired breath, and urine. After many years of research, no single marker sufficiently sensitive and specific for diagnosis of sarcoidosis has yet been found. Greater correlation with clinical parameters is needed and proper validation.     

Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS

Hepatic peptide hormone hepcidin is the key regulator of iron metabolism and the mediator of anemia of inflammation. Previous studies indicated that interleukin-6 (IL-6) mediates hepcidin increase and consequent hypoferremia during inflammation. Here we used an in vivo human endotoxemia model to analyze the effects of lipopolysaccharide (LPS) as a more upstream inflammation activator. The temporal associations between plasma cytokines, hepcidin levels, and serum iron parameters were studied in 10 healthy individuals after LPS injection. IL-6 was dramatically induced within 3 hours after injection, and urinary hepcidin peaked within 6 hours, followed by a significant decrease in serum iron. Serum prohepcidin showed no significant change within a 22-hour time frame. These in vivo human results confirm the importance of the IL-6-hepcidin axis in the development of hypoferremia in inflammation and highlight the rapid responsiveness of this iron regulatory system.     

Alcohol,inflammation,and gut-liver-brain interactions in tissue damage and disease development

Chronic inflammation is often associated with alcoholrelated medical conditions. The key inducer of such inflammation, and also the best understood, is gut microflora-derived lipopolysaccharide (LPS). Alcohol can significantly increase the translocation of LPS from the gut. In healthy individuals, the adverse effects of LPS are kept in check by the actions and interactions of multiple organs. The liver plays a central role in detoxifying LPS and producing a balanced cytokine milieu. The central nervous syst...     

Central Adiposity,Systemic Inflammation,and the Metabolic Syndrome

Metabolic syndrome (MetS) is a constellation of metabolic derangements and underlying factors that significantly increases the risk for developing type 2 diabetes and cardiovascular diseases. MetS is a low-grade inflammatory condition, with systemic inflammation and inflammation of central abdominal fat as contributors. Systemic inflammation in MetS is thought to involve C-reactive protein and some proinflammatory cytokines; the nuclear factor-κB pathway also is believed to play a role. Inflammation of central adipose tissue leads to adipokine production, followed by secretion of adipokines into the general circulation to contribute to the overall inflammatory condition. The molecular mechanisms that contribute to this inflammation are still somewhat unclear, but several serine/threonine kinases are known to be involved. Dietary components may also contribute to central adiposity and the inflammation seen in MetS.     

Systemic inflammation in colorectal cancer: Underlying factors,effects, and prognostic significance

Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.     

Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease

Cell death and inflammation are ancient processes of fundamental biological importance in both normal physiology and pathology. This is evidenced by the profound conservation of mediators, with ancestral homologues identified from plants to humans, and the number of diseases driven by aberrant control of either process. Apoptosis is the most well-studied cell death, but many forms exist, including autophagy, necrosis, pyroptosis, paraptosis, and the obscure dark cell death. Cell death occurs throughout the cardiovascular system, from initial shaping of the heart and vasculature during development to involvement in pathologies, including atherosclerosis, aneurysm, cardiomyopathy, restenosis, and vascular graft rejection. However, determining whether cell death primarily drives pathology or is a secondary bystander effect is difficult. Inflammation, the primary response of innate immunity, is considered essential in initiating and driving vascular diseases. Cell death and inflammation are inextricably linked with their effectors modulating the other process. Indeed, an evolutionary link between cell death and inflammation occurs at caspase-1 (which activates interleukin-1β), which can induce death by pyroptosis, and is a member of the caspase family vital for apoptosis. This review examines cell death in vascular disease, how it can induce inflammation, and finally the emergence of inflammasomes in vascular pathology.     

Osteoarthritis, angiogenesis and inflammation

Angiogenesis and inflammation are closely integrated processes in osteoarthritis (OA) and may affect disease progression and pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Angiogenesis can also promote chondrocyte hypertrophy and endochondral ossification, contributing to radiographic changes in the joint. Inflammation sensitizes nerves, leading to increased pain. Innervation can also accompany vascularization of the articular cartilage, where compressive forces and hypoxia may stimulate these new nerves, causing pain even after inflammation has subsided. Inhibition of inflammation and angiogenesis may provide effective therapeutics for the treatment of OA by improving symptoms and retarding joint damage. This review aims to summarize (i) the evidence that angiogenesis and inflammation play an important role in the pathophysiology of OA and (ii) possible directions for future research into therapeutics that could effectively treat this disease.     

Adiposity,Adipokines, and Exhaled Nitric Oxide in Healthy Adults Without Asthma

Background. Epidemiological studies have shown that obesity/adiposity is closely associated with asthma in terms of development, severity, and control of asthma. However, effects of obesity/adiposity on airway inflammation are not well known in subjects without asthma. We assessed whether fractional exhaled nitric oxide (FeNO), a marker of eosinophilic airway inflammation, was associated with obesity/adiposity in nonasthmatic healthy adults. Methods. We measured FeNO and serum levels of adipose-derived hormones and adipokines in 117 adult subjects without a previous diagnosis of asthma or current asthmatic symptoms. Associations between FeNO and measures of obesity/adiposity [body mass index (BMI), body fat mass, and body fat percentages] were examined by correlation analyses and uni- and multivariate linear regression analyses. Results. FeNO was not significantly associated with BMI, body fat mass, or body fat percentage by a multivariate linear regression model, adjusting for age, gender, chronic rhinitis, atopy, and lung function. No significant association of FeNO with serum levels of leptin, adiponectin, tumor necrosis factor (TNF)-α, or interleukin (IL)-6 was observed. Conclusions. These findings suggest that in healthy subjects without asthma, obesity/adiposity has no significant effect on eosinophilic airway inflammation and that hormones and systemic inflammation derived from adipose tissue do not affect eosinophilic airway inflammation.     

Impact of physical activity, cardiorespiratory fitness, and exercise training on markers of inflammation

Physical activity and exercise training (ET) enhance overall cardiorespiratory fitness (ie, fitness), thus producing many benefits in the primary and secondary prevention of cardiovascular diseases. Substantial evidence also indicates that acute and chronic inflammation is involved in the development and progression of atherosclerosis and major cardiovascular events. The most commonly utilized marker of inflammation is C-reactive protein (CRP). In this review, we discuss the importance of inflammation, especially CRP, as a cardiovascular risk marker by reviewing an abundant cross-sectional and clinical intervention literature providing evidence that physical activity, enhanced fitness, and ET are inversely associated with CRP and that being overweight or obese is directly related with inflammation/CRP. Although we discuss the controversy regarding whether or not ET reduces CRP independent of weight loss, clearly physical activity, improved fitness, and ET are associated with reductions in inflammation and overall cardiovascular risk in both primary and secondary prevention.     

Polyphenols, Inflammation, and Cardiovascular Disease

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.     

Changes in prealbumin, nutrient intake, and systemic inflammation in elderly recuperative care patients

OBJECTIVES: To determine the relationship between prealbumin, nutrient intake, and indicators of inflammation for recuperative and rehabilitative care patients.
DESIGN: Prospective cohort.
SETTING: Recuperative Care Unit within a Veterans Administration Nursing Home Care Unit.
PARTICIPANTS: One hundred eleven men (100 white; mean age 80, range 64–93).
MEASUREMENTS: Prealbumin and seven markers of inflammation (C-reactive protein (CRP), tumor necrosis factor, and interleukin-6 (IL-6) and their soluble receptors) were measured at admission and discharge (median length of stay 23 days, interquartile range 15–40 days). Detailed calorie counts were performed daily, and intake was expressed as a percentage of estimated requirements for protein (1.5 g/kg body weight per day) and energy (Harris-Benedict equation). The study objective was examined using least-squares regression analysis.
RESULTS: Discharge prealbumin and the change in prealbumin were positively correlated with protein and energy intake and inversely correlated with markers of inflammation, particularly CRP and IL-6. When all covariates were included in a multivariable regression analysis, the markers of inflammation predominantly accounted for the variance in prealbumin change (56%), whereas discharge protein intake accounted for 6%.
CONCLUSION: For older recuperative care patients, prealbumin and its change during hospitalization are positively associated with protein intake, but inflammation or changes in inflammation appear to exert a much more-powerful influence on prealbumin concentration. Given the potential confounding effects of inflammation, monitoring the change in prealbumin is not an adequate substitute for a more-detailed nutritional assessment in this population.     

Fcgamma receptors directly mediate cartilage, but not bone, destruction in murine antigen-induced arthritis: uncoupling of cartilage damage from bone erosion and joint inflammation

OBJECTIVE: To determine the relationship between synovial inflammation and the concomitant occurrence of cartilage and bone erosion during conditions of variable inflammation using various Fcgamma receptor knockout (FcgammaR(-/-)) mice. METHODS: Antigen-induced arthritis (AIA) was introduced in the knee joints of various FcgammaR(-/-) mice and wild-type controls. Joint inflammation and cartilage and bone destruction levels were determined by histologic analysis. Cathepsin K, RANKL, and osteoprotegerin (OPG) levels were detected by immunolocalization. RESULTS: In FcgammaRIIb(-/-) mice, which lack the inhibiting Fcgamma receptor IIb, levels of joint inflammation and cartilage and bone destruction were significantly higher (infiltrate 93%, exudate 200%, cartilage 100%, bone 156%). AIA in mice lacking activating FcgammaR types I, III, and IV, but not FcgammaRIIb (FcR gamma-chain(-/-) mice), prevented cartilage destruction completely. In contrast, levels of bone erosion and joint inflammation were comparable with their wild-type controls. Of great interest, in arthritic mice lacking activating FcgammaR types I, II, and III, but not IV (FcgammaRI/II/III(-/-) mice), levels of joint inflammation were highly elevated (infiltrate and exudate, 100% and 188%, respectively). Cartilage destruction levels were decreased by 92%, whereas bone erosion was increased by 200%. Cathepsin K, a crucial mediator of osteoclasts, showed a strong correlation with the amount of inflammation but not with the amount of activating FcgammaR, which was low in osteoclasts. RANKL, but not OPG, levels were higher in the inflammatory cells of arthritic knee joints of FcgammaRI/II/III(-/-) mice versus wild-type mice. CONCLUSION: Activating FcgammaR are crucial in mediating cartilage destruction independently of joint inflammation. In contrast, FcgammaR are not directly involved in bone erosion. Indirectly, FcgammaR drive bone destruction by regulating joint inflammation.     

Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction

OBJECTIVE: To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model. METHODS: Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically. RESULTS: Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL-1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra. CONCLUSION: Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.     

Inflammation,malnutrition and atherosclerosis in end-stage renal disease: a global perspective

End-stage renal disease (ESRD) is characterized by an exceptional cardiovascular mortality rate. Although traditional risk factors are common in ESRD patients, they alone may not be sufficient to account for the high prevalence of cardiovascular disease (CVD). Recent evidence demonstrated that chronic inflammation, a non-traditional risk factor which is commonly observed in ESRD patients, may cause malnutrition and progressive atherosclerotic CVD by several pathogenetic mechanisms. Although both malnutrition and inflammation have been shown to be strong predictors of cardiovascular mortality in ESRD patients, it must be remembered that the majority of studies describing the presence of inflammation and malnutrition have been performed in Western and Asian industrialized countries. As it is evident that the prevalence of malnutrition and inflammation may differ markedly between different regions of the world and developing countries face a much higher prevalence of chronic infectious diseases, comparative inter-regional studies focusing on the etiology and prevalence of the malnutrition, inflammation and atherosclerosis syndrome are warranted.