Chronic inflammation induced immunosuppression

Several different stimuli may induce chronic prostatic inflammation, which in turn would lead to tissue damage and continuous wound healing, thus contributing to prostatic enlargement. Patients with chronic inflammation and benign prostatic hyperplasia (BPH) have been shown to have larger prostate volumes, more severe lower urinary tract symptoms (LUTS) and a higher probability of acute urinary retention than their counterparts without inflammation. Chronic inflammation could be a predictor of poor response to BPH medical treatment. Thus, the ability to identify patients with chronic inflammation would be crucial to prevent BPH progression and develop target therapies. Although the histological examination of prostatic tissue remains the only available method to diagnose chronic inflammation, different parameters, such as prostatic calcifications, prostate volume, LUTS severity, storage and prostatitis-like symptoms, poor response to medical therapies and urinary biomarkers, have been shown to be correlated with chronic inflammation. The identification of patients with BPH and chronic inflammation might be crucial in order to develop target therapies to prevent BPH progression. In this context, clinical, imaging and laboratory parameters might be used alone or in combination to identify patients that harbour chronic prostatic inflammation.

The current study was performed to evaluate whether baseline acute and chronic prostate inflammation among men with an initial negative biopsy for prostate cancer (PCa) increased the risk of subsequent PCa detection in a clinical trial with systematic biopsies. A retrospective analysis was performed of 6238 men aged 50 years to 75 years with prostate-specific antigen levels between 2.5 ng/mL and 10 ng/mL and a prior negative biopsy in the REduction by DUtasteride of PCa Events study who completed a 2-year biopsy. PCa, acute prostate inflammation, and chronic prostate inflammation were assessed by central review. The association between inflammation in baseline prostate biopsies and positive 2-year and 4-year repeat biopsies was evaluated with the chi-square test and logistic regression analysis adjusting for baseline covariates. Acute and chronic inflammation and both were detected in 46 baseline biopsies (1%), 3931 baseline biopsies (63%), and 892 baseline biopsies (14%), respectively. Acute and chronic inflammation were found to be significantly associated with each other (P<.001). Acute inflammation at baseline biopsy was associated with younger age, lower prostate-specific antigen levels, and a smaller prostate (all P<.01), whereas chronic inflammation was associated with older age and larger prostate glands (all P<0.01). At the 2-year biopsy, the prevalence of PCa was 14% (N=900 patients). On univariable and multivariable analysis, both acute and chronic inflammation were found to be significantly associated with a lower PCa risk (acute univariable: odds ratio [OR], 0.65 [P<.001] and multivariable: OR, 0.75 [P=.012] and chronic univariable: OR, 0.61 [P<.001] and multivariable: OR, 0.65 [P<.001]). At the time of 4-year biopsy, only acute inflammation was found to be associated with a lower PCa risk. Baseline acute and chronic inflammation were both found to be independently associated with a lower PCa risk. From a clinical standpoint, inflammation in negative biopsies for PCa may lower the risk of subsequent PCa detection.

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health.

Smoking is associated with systemic and local inflammation in the lungs. Furthermore, in chronic obstructive pulmonary disease, which is often caused by smoking, there is often systemic inflammation that is linked to lung function impairment. However, the causal pathways linking smoking, systemic inflammation, and airflow limitation are still unknown. We tested whether higher tobacco consumption is associated with higher systemic inflammation, observationally and genetically and whether genetically higher systemic inflammation is associated with airflow limitation. We included 98085 individuals aged 20-100 years from the Copenhagen General Population Study; 36589 were former smokers and 16172 were current smokers. CHRNA3 rs1051730 genotype was used as a proxy for higher tobacco consumption and the IL6R rs2228145 genotype was used for higher systemic inflammation. Airflow limitation was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%. Difference in plasma level of C-reactive protein was 4.8% (95% CI = 4.4% to 5.2%) per 10 pack-year increase and 1.6% (95% CI = 0.4% to 2.8%) per T allele. Corresponding differences were 1.2% (95% CI = 1.1% to 1.3%) and 0.5% (95% CI = 0.3% to 0.8%) for fibrinogen, 1.2% (95% CI = 1.2% to 1.3%) and 0.7% (95% CI = 0.5% to 1.0%) for α1-antitrypsin, 2.0% (95% CI = 1.8% to 2.1%) and 0.7% (95% CI = 0.4% to 1.1%) for leukocytes, 1.9% (95% CI = 1.8% to 2.1%) and 0.8% (95% CI = 0.4% to 1.2%) for neutrophils, and 0.8% (95% CI = 0.7% to 1.0%) and 0.4% (95% CI = 0.1% to 0.7%) for thrombocytes. The differences in these levels were lower for former smokers compared with current smokers. The IL6R rs2228145 genotype was associated with higher plasma acute-phase reactants but not with airflow limitation. Compared with the C/C genotype, the odds ratio for airflow limitation was 0.95 (95% CI = 0.89 to 1.02) for A/C genotype and 0.94 (95% CI = 0.87 to 1.01) for A/A genotype. Higher tobacco consumption is associated with higher systemic inflammation both genetically and observationally, whereas systemic inflammation was not associated with airflow limitation genetically. The association between higher tobacco consumption and higher systemic inflammation may be causal, and the association is stronger among current smokers compared to former smokers, indicating that smoking cessation may reduce the effects of smoking on systemic inflammation. Systemic inflammation does not seem to be a causal driver in development of airflow limitation. These findings can help to understand the pathogenic effects of smoking and the interplay between smoking, systemic inflammation, and airflow limitation and hence development and progression of chronic obstructive pulmonary disease.

To evaluate whether baseline acute and chronic prostate inflammation among men with initial negative biopsy for prostate cancer (PC) is associated with PC volume at the 2-year repeat prostate biopsy in a clinical trial with systematic biopsies. Retrospective analysis of 886 men with negative baseline prostate biopsy and positive 2-year repeat biopsy in the Reduction by Dutasteride of PC Events (REDUCE) study. Acute and chronic inflammation and tumor volume were determined by central pathology. The association of baseline inflammation with 2-year repeat biopsy cancer volume was evaluated with linear and Poisson regressions controlling for demographics and laboratory variables. Chronic, acute inflammation, and both were detected in 531 (60%), 12 (1%), and 84 (9%) baseline biopsies, respectively. Acute and chronic inflammation were significantly associated with each other (P < 0.001). Chronic inflammation was associated with larger prostate (P < 0.001) and lower pre-repeat biopsy PSA (P = 0.01). At 2-year biopsy, baseline chronic inflammation was associated with lower mean tumor volume (2.07 µl vs. 3.15 µl; P = 0.001), number of biopsy cores involved (1.78 vs. 2.19; P < 0.001), percent of cores involved (17.8% vs. 22.8%; P < 0.001), core involvement (0.21 µl vs. 0.31 µl; P < 0.001), and overall percent tumor involvement (1.40% vs. 2.01%; P < 0.001). Results were unchanged in multivariable analysis. Baseline acute inflammation was not associated with any tumor volume measurement. In a cohort of men with 2-year repeat prostate biopsy positive for PC after a negative baseline biopsy, baseline chronic inflammation was associated with lower PC volume.

Serum surfactant protein D is increased in acute and chronic inflammation in mice

Objective.-To investigate the relationship between various histopathologic features and the results of the tuberculosis (TB)-polymerase chain reaction (PCR) method in routinely submitted histologic specimens for the histopathologic diagnosis of TB. Design.-We used 95 formalin-fixed, paraffin-embedded tissue blocks from 81 patients who were clinically suspected of having TB. We assessed the presence of histopathologic features including well-formed granuloma, poorly formed granuloma, caseous necrosis, and Langhans-type giant cells. We performed nested PCR for IS6110 and Ziehl-Neelsen staining for acid-fast bacilli (AFB). Results.-Of the 81 patients studied, 53 patients had chronic granulomatous inflammation, whereas 28 patients had only chronic inflammation without definite granulomatous inflammation. Of the 53 cases with chronic granulomatous inflammation, 17 (32%) were AFB positive and 36 (68%) were TB-PCR positive. Among cases with chronic granulomatous inflammation, the percentage that were positive and negative by TB-PCR differed significantly with the presence of various histopathologic features. All of the 13 cases with well-formed granuloma, caseous necrosis, and Langhans-type giant cells were TB-PCR positive; however, 10 (36%) of the 28 cases with chronic inflammation without granulomatous lesions were also TB-PCR positive. Conclusions.-TB-PCR is a rapid, sensitive method for the diagnosis of TB in routinely processed formalin-fixed, paraffin-embedded histologic specimens and is readily available in histopathology laboratories. We recommend use of TB-PCR when TB is suspected clinically, especially in cases of chronic inflammation without definite evidence of granulomatous inflammation.

Leptin, originally described as an adipocyte-derived hormone regulating energy expenditure, is now classified as a type I cytokine. We and others recently demonstrated that the lung is an additional source of leptin. The aim of the present study was to investigate the effect of acute and chronic inflammation on pulmonary expression of leptin in male Swiss mice. Acute lung inflammation was induced by a single intratracheal (IT) dose of 5 μg LPS (E.coli O55:B5), and mice were killed 4h, 24h and 72h postexposure. Chronic lung inflammation was induced by repeated LPS exposure (twice a week for 12 wks) and mice were killed after a 1-wk or 8-wks recovery period. Lungs were removed to assess cellular influx, leptin protein (immunohistochemistry) and mRNA (RT-PCR). Acute LPS exposure induced a transient neutrophilia (Vernooy, J.et al.AJRCMB 2001; 24:569–576). Chronic LPS exposure resulted in persistent accumulation of macrophages and CD8+ T-cells and emphysema (Vernooy, J.et al.AJRCMB 2002; 26:152–159). Control mice displayed positive leptin staining in bronchiolar epithelium and alveolar macrophages. Both acute (4h, 24h, 72h) and chronic (1-wk) inflammation was associated with complete suppression of pulmonary leptin expression at protein and mRNA level. Leptin expression was fully restored after 8-wks of recovery. Lungs of mice displayed constitutive leptin expression in bronchiolar epithelium and alveolar macrophages. Acute and chronic lung inflammation resulted in complete suppression of pulmonary leptin expression. Our data suggest that downregulation of leptin expression in lung may contribute to chronic pulmonary inflammation.

When Pathobiont-Carbohydrate Interaction Turns Bittersweet!

Helicobacter pylori is a common cause of gastritis. No single test is 100% accurate for H. pylori diagnosis. In order to determine whether the presence of typical histological features of H. pylori gastritis may yield diagnostic information, we compared antral histology by H & E stain to the presence of organisms as detected on Thiazine stain of antral specimens, CLOtest, urea breath test and anti-H. pylori serology in 50 consecutive patients. Patients were diagnosed as having active H. pylori infection if at least two of these tests were positive. Patients with only one test positive (N = 5) were considered indeterminate for H. pylori and were excluded, resulting in 19 patients (42%) being classified as H. pylori positive. All slides were reviewed by a single blinded expert gastrointestinal pathologist and graded 0 (none) to 3 (severe) for the presence of acute (polymorphonuclear cells) or chronic (lymphocytes, monocytes, plasma cells) inflammation, lymphoid aggregates, and intestinal metaplasia. Active infection was associated with the presence of both acute and chronic inflammation (P < 0.0001) but not lymphoid aggregates (P = 0.09) or intestinal metaplasia (P = 0.10). The best positive predictors of infection were the presence of any acute inflammation (PPV = 86%) and the combination of any acute and chronic inflammation (PPV = 92%). The best negative predictor was absence of chronic inflammation (NPV = 100%). The presence of moderate to severe (grade 2 or 3) acute or chronic inflammation were each 100% predictive of infection. Moderate to severe chronic inflammation had both 100% sensitivity and specificity for active H. pylori infection, while moderate to severe acute inflammation was only 26% sensitive but 100% specific. The presence of any acute, or the combination of acute and chronic gastritis, is predictive of active H. pylori infection. Moreover, the predictive value correlates closely with the severity of the inflammation. The absence of chronic inflammatory cells rules out active H. pylori infection. These findings support the use of H & E histology-determined features in conjunction with other tests to diagnose H. pylori infection.

Low first-trimester fetal fraction is associated with chronic inflammation in the placenta

Chapter 13 Neurophysiology of chronic inflammatory pain: electrophysiological recordings from spinal cord neurons in rats with prolonged acute and chronic unilateral inflammation at the ankle

Novel therapeutic strategies are needed to attenuate increased systemic and gut inflammation that contribute to morbidity and mortality in chronic HIV infection despite potent antiretroviral therapy (ART). The goal of this study is to use preclinical models of chronic treated HIV to determine whether the antioxidant and anti-inflammatory apoA-I mimetic peptides 6F and 4F attenuate systemic and gut inflammation in chronic HIV. We used two humanized murine models of HIV infection and gut explants from 10 uninfected and 10 HIV infected persons on potent ART, to determine the in vivo and ex vivo impact of apoA-I mimetics on systemic and intestinal inflammation in HIV. When compared to HIV infected humanized mice treated with ART alone, mice on oral apoA-I mimetic peptide 6F with ART had consistently reduced plasma and gut tissue cytokines (TNF-α, IL-6) and chemokines (CX3CL1) that are products of ADAM17 sheddase activity. Oral 6F attenuated gut protein levels of ADAM17 that were increased in HIV-1 infected mice on potent ART compared to uninfected mice. Adding oxidized lipoproteins and endotoxin (LPS) ex vivo to gut explants from HIV infected persons increased levels of ADAM17 in myeloid and intestinal cells, which increased TNF-α and CX3CL1. Both 4F and 6F attenuated these changes. Our preclinical data suggest that apoA-I mimetic peptides provide a novel therapeutic strategy that can target increased protein levels of ADAM17 and its sheddase activity that contribute to intestinal and systemic inflammation in treated HIV. The large repertoire of inflammatory mediators involved in ADAM17 sheddase activity places it as a pivotal orchestrator of several inflammatory pathways associated with morbidity in chronic treated HIV that make it an attractive therapeutic target.

Objective To improve the clinical understanding of intestinal Behcet’s disease. Methods A total of 43 patients with intestinal Behcet’s disease were collected from the First Affiliated Hospital of Zhengzhou University from January 2015 to April 2018. General information, clinical manifestations, laboratory tests, imaging examination and endoscopic characteristics were analyzed. Results Among these 43 patients with intestinal Behcet’s disease, 20 patients were males and 23 patients were females. The onset age was 13-57(32.79±11.70) years-old and the median course were 6 months. Gastrointestinal symptoms were presented after other systemic symptoms in 81.39% of the 43 patients. Abdominal pain (65.11%) was the most common clinical manifestations of intestinal involvement. Complications of alimentary system were gastrointestinal bleeding, intestinal perforation and intestinal obstruction. And the ratios of males to females in any ages were not significantly different (P>0.05). The lesion mainly located in ileocecal, terminal ileum and esophagus according to endoscopy. And the main manifestation under digestive endoscopy was anabrosis. Thirty-eight patients had histopathological examination. The main pathological features were mucosa chronic active inflammation with elcosis, lymphadenia, mucosa chronic nonspecific inflammation, proliferation of granulation tissue, chronic inflammation with necrosis and effusion, vasculitis, lymphoid follicular formation and focal granuloma. Thirty-five patients were treated with hormonal therapy, including single hormone therapy and combination with immunosuppressive agents or thalidomide. Most of the patients were relieved. The rest patients were not treated with hormones, but thalidomide or immunosuppressive agents was used, and most of them were relieved. Six cases underwent surgery, of which 2 cases underwent operation for perforation, 1 case for cancer, 1 case for misdiagnosis as colon cancer , 1 case for misdiagnosis as ulcerative colitis and 1 case for performance of perianal cyst resection. Conclusions The clinical manifestations of intestinal Behcet’s disease are diverse. Most of the symptoms of the digestive system occurs after systemic manifestations, so this disease is often missed or misdiagnosed as other diseases due to non-specific performance in clinical. Some patients may have severe complications. In clinical, the understanding of intestinal Behcet’s disease should be strengthened to avoid misdiagnosis and missed diagnosis. Key words: Intestinal Behcet’s disease; Clinical manifestation; Endoscopic characters

In this study, the anti-nociceptive and anti-inflammatory effects of cyanocobalamin (Vit B12) against acute and chronic pain and inflammation were evaluated in mice. Vit B12 (0.87, 1 and 1.77 mg/kg) were injected intraperitoneally. The anti-nociceptive effects against acute pain were examined using hot-plate and writhing tests. The chronic pain was examined 14 days after sciatic nerve ligation using the hot-plate test. Morphine (10 mg/kg) was used as a positive control. Anti-inflammatory effects of Vit B12 against acute and chronic inflammation were assessed using xylene-induced edema in ears and granuloma caused by compressed cotton implantation, respectively. In these tests, sodium diclofenac (15 mg/kg) was used as a positive control. Vit B12 showed a dose related effect in acute anti-nociceptive test and increased the anti-nociceptive effect of morphine in chronic treatment. Vit B12 demonstrated an anti-nociceptive effect in chronic studies as single or continues daily treatment and increased significantly the anti-nociceptive effect of morphine. All doses of Vit B12 significantly decreased xylene-induced ear edema. Maximum anti-inflammatory effect (37.5%) was obtained at dose of 1 mg/kg. In chronic inflammation, Vit B12 significantly decreased granuloma formation in mice. In conclusion our work presents some experimental evidence supporting the administration of cyanocobalamin in controlling acute and chronic neuropathic pain. Cyanocobalamin may have anti-inflammatory effect. It may reduce tolerance to anti-nociceptive effect of morphine as well.