Procalcitonin has been shown to be useful in separating infection from non-infective disorders. However, infection is often paralleled by tissue inflammation. Most studies supporting the use of procalcitonin were confounded by more significant inflammation in the infection group. Few studies have examined the usefulness of procalcitonin when adjusted for inflammation.
Pleural inflammation underlies the development of most exudative effusions including pleural infection and malignancy. Pleurodesis, often used to treat effusions, involves provocation of intense aseptic pleural inflammation. We conducted a two-part proof-of-concept study to test the specificity of procalcitonin in differentiating infection using cohorts of patients with pleural effusions of infective and non-infective etiologies, as well as subjects undergoing pleurodesis.
We measured the blood procalcitonin level (i) in 248 patients with pleural infection or with non-infective pleural inflammation, matched for severity of systemic inflammation by C-reactive protein (CRP), age and gender; and (ii) in patients before and 24–48 hours after induction of non-infective pleural inflammation (from talc pleurodesis).
1) Procalcitonin was significantly higher in patients with pleural infection compared with controls with non-infective effusions (n = 32 each group) that were case-matched for systemic inflammation as measured by CRP [median (25–75%IQR): 0.58 (0.35–1.50) vs 0.34 (0.31–0.42) µg/L respectively, p = 0.003]. 2) Talc pleurodesis provoked intense systemic inflammation, and raised serum CRP by 360% over baseline. However procalcitonin remained relatively unaffected (21% rise). 3) Procalcitonin and CRP levels did not correlate. In 214 patients with pleural infection, procalcitonin levels did not predict the survival or need for surgical intervention.
Using a pleural model, this proof-of-principle study confirmed that procalcitonin is a biomarker specific for infection and is not affected by non-infective inflammation. Procalcitonin is superior to CRP in distinguishing infection from non-infective pleural diseases, even when controlled for the level of systemic inflammation.
Studies have been described in which the effect of early and late or established inflammation, upon staphylococcus infection of rabbit skin has been evaluated. Inflammation was produced in skin by thermal, chemical, bacterial and immunological injury, and it was found that the area of inflammation was more susceptible to staphylococcus infection than was normal skin if the bacteria were injected within 2 to 3 days after the injury. When staphylococci were injected into an area of inflammation of over 3 days' duration, there appeared to be an increase in local resistance to infection. The way in which inflammation was produced seemed to have a little influence upon the effects observed. This influence of non-specific inflammation upon staphylococcus infection was compared with the influence of specific bacterial hypersensitivity, which also is associated with an increase in infectivity of the microorganism in sensitized animals. It was concluded that specific bacterial hypersensitivity probably increases susceptibility to infection with the staphylococcus in the same way as non-specific inflammation. The general significance of non-specific inflammation upon infection is also discussed.
The mechanisms underlying exacerbation of asthma induced by respiratory syncytial virus (RSV) infection have been extensively studied in human and animal models. However, most of these studies focused on acute inflammation and little is known of its long-term consequences on remodelling of the airway tissue.
The aim of the study was to use a murine model of prolonged allergen-induced airway inflammation to investigate the effect of RSV infection on allergic airway inflammation and tissue remodelling.
We subjected mice to RSV infection before or during the chronic phase of airway challenges with OVA and compared parameters of airway inflammation and remodelling at the end-point of the prolonged allergen-induced airway inflammation protocol.
RSV infection did not affect the severity of airway inflammation in any of the groups studied. However, RSV infection provoked airway remodelling in non-sensitized, allergen-challenged mice that did not otherwise develop any of the features of allergic airways disease. Increased collagen synthesis in the lung and thickening of the bronchial basal membrane was observed in non-sensitized allergen-challenged mice only after prior RSV infection. In addition, fibroblast growth factor (FGF)-2 but not TGF-β1 was increased in this group following RSV infection.
Our data show for the first time that RSV infection can prime the lung of mice that are not previously systemically sensitized, to develop airway remodelling in response to allergen upon sole exposure via the airways. Moreover, our results implicate RSV-induced FGF-2 in the remodelling process in vivo.
airway allergic inflammation; airway remodelling; asthma; RSV
Inflammation is the body’s response to insults, which include infection, trauma, and hypersensitivity. The inflammatory response is complex and involves a variety of mechanisms to defend against pathogens and repair tissue. In the lung, inflammation is usually caused by pathogens or by exposure to toxins, pollutants, irritants, and allergens. During inflammation, numerous types of inflammatory cells are activated. Each releases cytokines and mediators to modify activities of other inflammatory cells. Orchestration of these cells and molecules leads to progression of inflammation. Clinically, acute inflammation is seen in pneumonia and acute respiratory distress syndrome (ARDS), whereas chronic inflammation is represented by asthma and chronic obstructive pulmonary disease (COPD). Because the lung is a vital organ for gas exchange, excessive inflammation can be life threatening. Because the lung is constantly exposed to harmful pathogens, an immediate and intense defense action (mainly inflammation) is required to eliminate the invaders as early as possible. A delicate balance between inflammation and anti-inflammation is essential for lung homeostasis. A full understanding of the underlying mechanisms is vital in the treatment of patients with lung inflammation. This review focuses on cellular and molecular aspects of lung inflammation during acute and chronic inflammatory states.
inflammation; lung; inflammatory mediators; cytokines
Assessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C-reactive protein) to represent inflammation may not be appropriate in HIV/HCV co-infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers.
We compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use.
Detectable HIV and HCV RNA (OR = 2.49; 95% CI = 1.05–5.89) and detectable HCV RNA alone (2.95; 1.08–8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90–31.97) and TNF-α (7.70; 1.42–41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84).
Detectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities.
HIV; HCV; Inflammation; Alcohol; Liver; Comorbidity
Properly regulated inflammation facilitates recognition and reaction to injury or infection, but inadequate or overly robust inflammation can lead to disease. Sepsis is an inflammatory disease that accounts for nearly 10% of total U.S. deaths, costing more than $17 billion. Acute inflammation in sepsis may evolve too rapidly to be modulated appropriately, and we suggest that therapies should focus not on abolishing inflammation, but rather on attenuating the positive feedback cycle of inflammation/damage/inflammation. In Gram-negative sepsis, bacterial endotoxin causes inflammation and is driven and regulated by the cytokine tumor necrosis factor-α (TNF-α), which is, in turn, negatively regulated via its endogenous inhibitor, soluble TNF-α receptor (sTNFR). We generated stably gene-modified variants of human HepG2 hepatocytes, using lentiviral constructs coding for mouse sTNFR driven by the constitutive cytomegalovirus promoter, and seeded them in a scaled-down, experimental liver bioreactor. When connected to anesthetized, cannulated rats subjected to endotoxin infusion and maintained solely by the animals’ circulation, this biohybrid device elevated circulating sTNFR, reduced the levels of TNF-α and other key inflammatory mediators, alleviated hypotension, and reduced circulating markers of organ damage. This novel class of biohybrid devices may bemodified for patient- and disease-specific application, and, thus, may represent a disruptive strategy that offers the potential for rational inflammation reprogramming.
soluble tumor necrosis factor-alpha receptor 1; tumor necrosis factor alpha; endotoxin; sepsis; biohybrid device; multiple organ dysfunction syndrome
Several human cancers are known to be associated with inflammation and/or viral infections. However, the influence of tumour-related inflammation on viral uptake is largely unknown. In this study we used oesophageal squamous cell carcinoma (OSCC) as a model system since this type of cancer is associated with chronic irritation, inflammation and viral infections. Although still debated, the most important viral infection seems to be with Human Papillomavirus (HPV). The present study focused on a possible correlation between inflammation, OSCC development and the influence of HPV infection.
A total of 114 OSCC biopsies and corresponding normal tissue were collected at Groote Schuur Hospital and Tygerberg Hospital, Cape Town (South Africa), that were subjected to RNA and DNA isolation. RNA samples were analysed by quantitative Light Cycler RT-PCR for the expression of selected genes involved in inflammation and infection, while conventional PCR was performed on the DNA samples to assess the presence of integrated viral DNA. Further, an in vitro infection assay using HPV pseudovirions was established to study the influence of inflammation on viral infectivity using selected cell lines.
HPV DNA was found in about 9% of OSCC patients, comprising predominantly the oncogenic type HPV18. The inflammatory markers IL6 and IL8 as well as the potential HPV receptor ITGA6 were significantly elevated while IL12A was downregulated in the tumour tissues. However, none of these genes were expressed in a virus-dependent manner. When inflammation was mimicked with various inflammatory stimulants such as benzo-α-pyrene, lipopolysaccharide and peptidoglycan in oesophageal epithelial cell lines in vitro, HPV18 pseudovirion uptake was enhanced only in the benzo-α-pyrene treated cells. Interestingly, HPV pseudovirion infectivity was independent of the presence of the ITGA6 receptor on the surface of the tested cells.
This study showed that although the carcinogen benzo-α-pyrene facilitated HPV pseudovirion uptake into cells in culture, HPV infectivity was independent of inflammation and seems to play only a minor role in oesophageal cancer.
HPV; Cytokines; Receptors; Oesophageal cancer
Chagas’ disease is caused by Trypanosoma cruzi infection and is characterized by chronic fibrogenic inflammation and heart dysfunction. Chemokines are produced during infection and drive tissue inflammation. In rats, acute infection is characterized by intense myocarditis and regression of inflammation after control of parasitism. We investigated the role of CCL3 and CCL5 during infection by using DNA vaccination encoding for each chemokine separately or simultaneously. MetRANTES treatment was used to evaluate the role of CCR1 and CCR5, the receptors for CCL3 and CCL5. Vaccination with CCL3 or CCL5 increased heart parasitism and decreased local IFN-γ production, but did not influence intensity of inflammation. Simultaneous treatment with both plasmids or treatment with MetRANTES enhanced cardiac inflammation, fibrosis and parasitism. In conclusion, chemokines CCL3 and CCL5 are relevant, but not essential, for control of T. cruzi infection in rats. On the other hand, combined blockade of these chemokines or their receptors enhanced tissue inflammation and fibrosis, clearly contrasting with available data in murine models of T. cruzi infection. These data reinforce the important role of chemokines during T. cruzi infection but suggest that caution must be taken when expanding the therapeutic modulation of the chemokine system in mice to the human infection.
Chemokines; CCR5; Trypanosoma cruzi; Myocarditis
Chronic airway infection and inflammation are hallmarks of cystic fibrosis (CF) pulmonary disease. The altered airway environment resulting from infection and inflammation can affect the innate defense of the airway epithelia. Luminal bacterial and inflammatory stimuli trigger an adaptation in human airway epithelia, characterized by a hyperinflammatory response to inflammatory mediators, which is mediated by an expansion of the endoplasmic reticulum (ER) and its Ca2+ stores. Recent studies demonstrated that a form of ER stress, the unfolded protein response (UPR), is activated in airway epithelia by bacterial infection–induced airway inflammation. UPR-dependent signaling is responsible for the ER Ca2+ store expansion-mediated amplification of airway inflammatory responses. These studies highlight the functional importance of the UPR in airway inflammation and suggest that targeting the UPR may be a therapeutic strategy for airway diseases typified by chronic inflammation. This article reviews the contribution of airway epithelia to airway inflammatory responses, discusses how expansion of the ER Ca2+ stores in inflamed airway epithelia contributes to airway inflammation, describes the functional role of the UPR in these processes, and discusses how UPR activation might be relevant for CF airways inflammatory disease.
airway inflammation; airway epithelia; cystic fibrosis; endoplasmic reticulum calcium stores; unfolded protein response
Inflammation is by definition a protective phase of the immune response. The very first goal of inflammation is destroying and phagocytosing infected or damaged cells to avoid the spread of the pathogen or of the damage to neighboring, healthy, cells. However, we now know that during many chronic neurological disorders, inflammation and degeneration always coexist at certain time points. For example, inflammation comes first in multiple sclerosis, but degeneration follows, while in Alzheimer's or Parkinson's disease degeneration starts and inflammation is secondary. Either way these are the two pathological detectable problems. The central nervous system (CNS) has long been viewed as exempt from the effects of the immune system. The brain has physical barriers for protection, and it is now clear that cells in the nervous system respond to inflammation and injury in unique ways. In recent years, researchers have presented evidence supporting the idea that in the CNS there is an ongoing protective inflammatory mechanism, which involves macrophage, monocytes, T cells, regulatory T-cells, effector T cells and many others; these, in turn, promote repair mechanisms in the brain not only during inflammatory, and degenerative disorders but also in healthy people. This “repair mechanism” can be considered as an intrinsic part of the physiological activities of the brain. It is now well known that the microenvironment of the brain is a crucial player in determining the relative contribution of the two different outcomes. Failure of molecular and cellular mechanisms sustaining the “brain-repair programme” might be, at least in part, a cause of neurological disorders. Today, the neurotoxic and neuroprotective roles of the innate immune reactions in aging, brain injury, ischemia, autoimmune and neurodegenerative disorders of the CNS are widely investigated and highly debated research topics. Nevertheless, several issues remain to be elucidated, notably the earlier cellular events that initiate dysregulation of brain inflammatory pathways. If these inflammatory processes could be identified and harnessed, then cognitive function may be protected during aging and age-related neurodegenerative diseases through early interventions directed against the negative consequences of inflammation. This commentary highlights the major issues/opinions presented by experts on the involvement of the brain immune system in aging and age-related diseases in a special edition of the journal Aging and Disease.
Aging; Neuroinflammation; Immune system; Brain
Inflammatory disorders account for a significant percentage of gynecologic disease, particularly in reproductive age women. Inflammation is a basic method by which we respond to infection, irritation, or injury. Inflammation is now recognized as a type of nonspecific immune response, either acute or chronic. In gynecology, inflammation leads to anatomic disorders primarily as a result of infectious disease; however inflammation can affect ovulation and hormone production as well as be associated with endometriosis. Similarly, immune cell trafficking is an important component of cyclic endometrial development in each menstrual cycle. These immune cells are required for endometrial function, producing a vast array of inflammatory cytokines. Inflammation alters endometrial receptivity, however it may also play a role in tissue repair and remodeling. Finally, inflammation affects the trophoblast and trophoblast—endometrial interaction. Some components of the immune response are required for optimal fertility and normal tissue remodeling. A better understanding of the necessary role of inflammation in reproduction will allow more rational and targeted treatment of inflammatory disorders in reproductive medicine.
Reproduction; inflammation; ovulation; infertility; implantation
Inflammation is by definition a protective phase of the immune response. The very first goal of inflammation is destroying and phagocytosing infected or damaged cells to avoid the spread of the pathogen or of the damage to neighboring, healthy, cells. However, we now know that during many chronic neurological disorders, inflammation and degeneration always coexist at certain time points. For example, inflammation comes first in multiple sclerosis, but degeneration follows, while in Alzheimer’s or Parkinson’s disease degeneration starts and inflammation is secondary. Either way these are the two pathological detectable problems. The central nervous system (CNS) has long been viewed as exempt from the effects of the immune system. The brain has physical barriers for protection, and it is now clear that cells in the nervous system respond to inflammation and injury in unique ways. In recent years, researchers have presented evidence supporting the idea that in the CNS there is an ongoing protective inflammatory mechanism, which involves macrophage, monocytes, T cells, regulatory T-cells, effector T cells and many others; these, in turn, promote repair mechanisms in the brain not only during inflammatory, and degenerative disorders but also in healthy people. This “repair mechanism” can be considered as an intrinsic part of the physiological activities of the brain. It is now well known that the microenvironment of the brain is a crucial player in determining the relative contribution of the two different outcomes. Failure of molecular and cellular mechanisms sustaining the “brain-repair programme” might be, at least in part, a cause of neurological disorders. Today, the neurotoxic and neuroprotective roles of the innate immune reactions in aging, brain injury, ischemia, autoimmune and neurodegenerative disorders of the CNS are widely investigated and highly debated research topics. Nevertheless, several issues remain to be elucidated, notably the earlier cellular events that initiate dysregulation of brain inflammatory pathways. If these inflammatory processes could be identified and harnessed, then cognitive function may be protected during aging and age-related neurodegenerative diseases through early interventions directed against the negative consequences of inflammation. This commentary highlights the major issues/opinions presented by experts on the involvement of the brain immune system in aging and age-related diseases in a special edition of the journal Aging and Disease.
Aging; Neuroinflammation; Immune system; Brain
Liver inflammation due to HCV infection leads to fibrosis, which is an independent predictor of treatment response to interferon therapy in Chronic Hepatitis C (CHC) patients. This relationship has not been studied for liver inflammation on pretreatment liver biopsy and End of Treatment Response (ETR). ALT is a less invasive test than liver biopsy for measuring liver inflammation. Aim of this study was to compare ETR to Interferon α (recombinant Interferon) & Ribavirin in CHC patients having higher and lower grades of liver inflammation and to determine the diagnostic accuracy of pretreatment ALT for grades of liver inflammation.
A retrospective cohort of 876 naïve CHC patients, who completed Interferon α & Ribavirin for 24 weeks, was studied for ETR. Pretreatment grade of inflammation on liver biopsy was taken as the exposure variable. It was classified as high if there was moderate or severe and low if there was minimal or mild. Multivariable logistic regression modeling was performed. Diagnostic accuracy of pretreatment ALT for liver inflammation grades was determined by computing Area Under the Receiver Operator Curve (AUROC).
Of all patients, 672 having diagnostic liver biopsy and ETR available were analyzed. Among them, 103 had high and 569 had low grades of liver inflammation. Mean age was 36.9 (SD 9.1) years, with patients with high grades being older than those with low grades inflammation (p = 0.03). High grades of liver inflammation was associated with ETR (RR 1.17, 95% CI 1.12–1.18) adjusting for age, Total Leukocyte count (TLC) and pretreatment levels of ALT, irrespective of liver fibrosis. This relation remained significant for ‘bridging fibrosis and cirrhosis’ and not for ‘no’ or ‘portal fibrosis’. AUROC of pretreatment ALT for males and females was moderately accurate for severe inflammation compared to minimal inflammation and less accurate for high grades compared to low grades.
ETR in patients with higher grades of liver inflammation was 17% higher than those with lower grades irrespective of fibrosis and 9% higher for bridging fibrosis and cirrhosis. Pretreatment ALT was moderately accurate for severe inflammation only on liver biopsy in both males and females.
Inflammation and angiogenesis are integral parts of wound healing. However, excessive and persistent wound-induced inflammation and angiogenesis in an avascular tissue such as the cornea may be associated with scarring and visual impairment. Junctional adhesion molecule A (Jam-A) is a tight junction protein that regulates leukocyte transmigration as well as fibroblast growth factor-2 (FGF-2)-induced angiogenesis. However its function in wound-induced inflammation and angiogenesis is still unknown. In this study, we report spontaneous corneal opacity in Jam-A deficient mice associated with inflammation, angiogenesis and the presence of myofibroblasts. Since wounds and/or corneal infections cause corneal opacities, we tested the role of Jam-A in wound-induced inflammation, angiogenesis and scarring by subjecting Jam-A deficient mice to full thickness corneal wounding. Analysis of these wounds demonstrated increased inflammation, angiogenesis, and increased number of myofibroblasts thereby indicating that Jam-A regulates the wound-healing response by controlling wound-induced inflammation, angiogenesis and scarring in the cornea. These effects were not due to inflammation alone since the inflammation-induced wound-healing response in Jam-A deficient mice was similar to wild type mice. In order to determine the molecular mechanism associated with the observed aberrant corneal wound healing in Jam-A deficient mice, we assessed the expression of the components of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor- 2(VEGFR-2) signaling pathway. Interestingly, we observed increased levels of VEGF-A mRNA in Jam-A deficient eyes. We also observed nuclear localization of phosphorylated SMAD3 (pSMAD3) indicative of TGFβ pathway activation in the Jam-A deficient eyes. Furthermore the increased wound-induced corneal inflammation, angiogenesis, and scarring in Jam-A deficient mice was attenuated by treatment with DC101, an anti-vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. Our results suggest that in the absence of Jam-A, the VEGF-A/VEGFR-2 pathway is upregulated, thereby augmenting wound induced corneal inflammation, angiogenesis, and myofibroblast accumulation leading to scarring.
We assessed foreskin inflammation associated with HIV and herpes simplex virus type 2 (HSV-2) in circumcised men.
Foreskin tissues were assessed in 97 HIV-infected and 135 HIV-uninfected men enrolled in randomized trials of circumcision in Rakai, Uganda. Inflammation was quantified using an ordinal score evaluating extent, intensity, and cellular composition of infiltrates in the epithelium and stroma. Prevalence rate ratios of inflammation were estimated by multivariate Poisson regression.
Foreskin inflammation was primarily focal. Epithelial inflammation was present in 4.2% of men with neither HIV nor HSV-2 infection; 7.8% of men with only HSV-2; 19.0% with HIV alone (P=0.04); and 31.6% in HIV/HSV-2 coinfected men [prevalence rate ratio (PRR) 7.5, 95% confidence interval (CI) 2.3-23.8, P<0.001]. Stromal inflammation was present in 14.1% of HIV/HSV-2 uninfected men, compared with 29.7% in men with HSV-2 alone (P=0.03), 33.3% in men with HIV alone (P=0.04), and 61.0% in men with HIV/HSV-2 coinfection (PRR 4.3, 95% CI 2.3-7.9, P<0.001). In HIV-infected men, epithelial inflammation was associated with higher HIV viral load. Epithelial inflammation was more frequent among men reporting recent genital ulceration. Both epithelial and stromal inflammation were more common among men with smegma on physical examination.
Foreskin inflammation is increased with HIV and HSV-2 infections, higher HIV viral load and presence of smegma. Foreskin inflammation may have implications for HIV transmission and acquisition in uncircumcised men.
circumcision; foreskin; HIV; herpes simplex virus type 2; inflammation; Uganda
Inflammation is a key feature of HIV infection and is correlated with long-term negative cardiovascular outcomes. Therapy-induced increases in CD4+ cell counts can control inflammation, as shown by decreases of coagulation and inflammation markers during efficacious therapy. Maraviroc, a CCR5-antagonist, has resulted in larger increases in CD4+ counts both in naïve and experienced subjects compared to traditional antiretroviral therapy.
Objectives and Methods
To examine if a member of the protein C anticoagulant and anti-inflammatory pathway, and marker of coagulation and inflammation, the soluble endothelial protein C receptor, is modified by infection and therapy-related variables in patients treated with Maraviroc. Endothelial protein C receptor, together with other established markers of inflammation and coagulation (CRP, IL-6, D-dimer and soluble thrombomodulin) was studied in 43 patients on traditional antiretroviral therapy and in 45 on Maraviroc during 48 weeks of follow-up.
Soluble endothelial protein C receptor was the only marker that could discriminate at least partially between patients with a good response to Maraviroc and patients who did not respond with an adequate increase in CD4+ cell counts (more than 500 cells/µL by week 48).
Elevated levels of soluble endothelial protein C receptor, a sensitive marker of endothelial damage, indicated a low level of inflammation and coagulation activation in Maraviroc treated patients not picked up by other widely used markers. Persistent elevated levels of this marker at 48 weeks from beginning of treatment with Maraviroc were related to a poor increase in CD4+ cells.
The secreted goblet cell-derived protein resistin-like molecule β (RELMβ) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMβ influences CD4+ T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMβ in augmenting CD4+ Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-γ production and intestinal inflammation. In contrast, infected RELMβ−/− mice exhibited a significantly reduced expression of parasite-specific CD4+ T cell-derived IFN-γ and TNF-α and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMβ activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN-γ expression in CD4+ T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMβ, can promote adaptive CD4+ T cell responses and chronic inflammation following intestinal helminth infection.
Salmonella enterica subspecies 1 serovar Typhimurium (S. Typhimurium) causes diarrhea and acute inflammation of the intestinal mucosa. The pro-inflammatory cytokines IL-17A and IL-17F are strongly induced in the infected mucosa but their contribution in driving the tissue inflammation is not understood. We have used the streptomycin mouse model to analyze the role of IL-17A and IL-17F and their cognate receptor IL-17RA in S. Typhimurium enterocolitis. Neutralization of IL-17A and IL-17F did not affect mucosal inflammation triggered by infection or spread of S. Typhimurium to systemic sites by 48 h p.i. Similarly, Il17ra−/− mice did not display any reduction in infection or inflammation by 12 h p.i. The same results were obtained using S. Typhimurium variants infecting via the TTSS1 type III secretion system, the TTSS1 effector SipA or the TTSS1 effector SopE. Moreover, the expression pattern of 45 genes encoding chemokines/cytokines (including CXCL1, CXCL2, IL-17A, IL-17F, IL-1α, IL-1β, IFNγ, CXCL-10, CXCL-9, IL-6, CCL3, CCL4) and antibacterial molecules was not affected by Il17ra deficiency by 12 h p.i. Thus, in spite of the strong increase in Il17a/Il17f mRNA in the infected mucosa, IL-17RA signaling seems to be dispensable for eliciting the acute disease. Future work will have to address whether this is attributable to redundancy in the cytokine signaling network.
We investigated the association between human immunodeficiency virus (HIV) and prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation in a cohort of HIV-infected and uninfected veterans who had a comparable burden of comorbid conditions.
Background. Biomarkers of inflammation, altered coagulation, and monocyte activation are associated with mortality and cardiovascular disease (CVD) in the general population and among human immunodeficiency virus (HIV)–infected people. We compared biomarkers for inflammation, altered coagulation, and monocyte activation between HIV-infected and uninfected people in the Veterans Aging Cohort Study (VACS).
Methods. Biomarkers of inflammation (interleukin-6 [IL-6]), altered coagulation (d-dimer), and monocyte activation (soluble CD14 [sCD14]) were measured in blood samples from 1525 HIV-infected and 843 uninfected VACS participants. Logistic regression was used to determine the association between HIV infection and prevalence of elevated (>75th percentile) biomarkers, adjusting for confounding comorbidities.
Results. HIV-infected veterans had less prevalent CVD, hypertension, diabetes, obesity, hazardous drinking, and renal disease, but more dyslipidemia, hepatitis C, and current smoking than uninfected veterans. Compared to uninfected veterans, HIV-infected veterans with HIV-1 RNA ≥500 copies/mL or CD4 count <200 cells/µL had a significantly higher prevalence of elevated IL-6 (odds ratio [OR], 1.54; 95% confidence interval [CI],1.14–2.09; OR, 2.25; 95% CI, 1.60–3.16, respectively) and d-dimer (OR, 1.97; 95% CI, 1.44–2.71, OR, 1.68; 95% CI, 1.22–2.32, respectively) after adjusting for comorbidities. HIV-infected veterans with a CD4 cell count <200 cells/µL had significantly higher prevalence of elevated sCD14 compared to uninfected veterans (OR, 2.60; 95% CI, 1.64–4.14). These associations still persisted after restricting the analysis to veterans without known confounding comorbid conditions.
Conclusions. These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions.
Urinary catheterization elicits major histological and immunological changes that render the bladder susceptible to microbial invasion, colonization, and dissemination. However, it is not understood how catheters induce these changes, how these changes act to promote infection, or whether they may have any protective benefit. In the present study, we examined how catheter-associated inflammation impacts infection by Enterococcus faecalis, a leading cause of catheter-associated urinary tract infection (CAUTI), a source of significant societal and clinical challenges. Using a recently optimized murine model of foreign body-associated UTI, we found that the implanted catheter itself was the primary inducer of inflammation. In the absence of the silicone tubing implant, E. faecalis induced only minimal inflammation and was rapidly cleared from the bladder. The catheter-induced inflammation was only minimally altered by subsequent enterococcal infection and was not suppressed by inhibitors of the neurogenic pathway and only partially by dexamethasone. Despite the robust inflammatory response induced by urinary implantation, E. faecalis produced biofilm and high bladder titers in these animals. Induction of inflammation in the absence of an implanted catheter failed to promote infection, suggesting that the presence of the catheter itself is essential for E. faecalis persistence in the bladder. Immunosuppression prior to urinary catheterization enhanced E. faecalis colonization, suggesting that implant-mediated inflammation contributes to the control of enterococcal infection. Thus, this study underscores the need for novel strategies against CAUTIs that seek to reduce the deleterious effects of implant-mediated inflammation on bladder homeostasis while maintaining an active immune response that effectively limits bacterial invaders.
This article discusses the current techniques and future directions of infection imaging with particular attention to respiratory, CNS, abdominal, and postoperative infections. The agents currently in use localize to areas of infection and inflammation. An infection specific imaging agent would greatly improve the utility of scintigraphy in imaging occult infections. The superior spatial resolution of 18F-FDG PET and its lack of reliance on a functional immune system, gives this agent certain advantages over the other radiopharmaceuticals.
In respiratory infection imaging, an important advancement would be the ability to quantitatively delineate lung inflammation, allowing one to monitor the therapeutic response in a variety of conditions. Current studies suggest PET should be considered the most accurate quantitative method.
Scintigraphy has much to offer in localizing abdominal infection as well as inflammation. We may begin to see a gradual increase in the usage of FDG PET in detecting occult abdominal infections. Commonly used modalities for imaging inflammatory bowel disease are scintigraphy with 111In-oxine/99mTc-HMPAO labeled autologous white blood cells.
The literature on CNS infection imaging is relatively scarce. Few clinical studies have been performed and numerous new agents have been developed for this use with varying results. Further studies are needed to more clearly delineate the future direction of this field.
In evaluating the post-operative spine, 99mTc-ciprofloxacin SPECT was reported to be >80% sensitive in patients more than 6 months post-surgery. FDG PET has also been suggested for this purpose and may play a larger role than originally thought.
It appears PET/CT is gaining support, especially in imaging those with fever of unknown origin or nonfunctional immune systems. While an infection specific agent is lacking, the development of one would greatly advance our ability to detect, localize, and quantify infections. Overall, imaging such an agent via SPECT/CT or PET/CT will pave the way for greater clinical reliability in the localization of infection.
The association between chronic inflammation and cancer is now well established. This association has recently received renewed interest with the recognition that microbial pathogens can be responsible for the chronic inflammation observed in many cancers, particularly those originating in the gastrointestinal system. A prime example is Helicobacter pylori, which infects 50% of the world’s population and is now known to be responsible for inducing chronic gastric inflammation that progresses to atrophy, metaplasia, dysplasia, and gastric cancer. This Review provides an overview of recent progress in elucidating the bacterial properties responsible for colonization of the stomach, persistence in the stomach, and triggering of inflammation, as well as the host factors that have a role in determining whether gastritis progresses to gastric cancer. We also discuss how the increased understanding of the relationship between inflammation and gastric cancer still leaves many questions unanswered regarding recommendations for prevention and treatment.
Humans inhale hundreds of Aspergillus conidia without adverse consequences. Powerful protective mechanisms may ensure prompt control of the pathogen and inflammation. Here we reveal a previously unknown mechanism by which the danger molecule S100B integrates pathogen– and danger–sensing pathways to restrain inflammation. Upon forming complexes with TLR2 ligands, S100B inhibited TLR2 via RAGE, through a paracrine epithelial cells/neutrophil circuit that restrained pathogen-induced inflammation. However, upon binding to nucleic acids, S100B activated intracellular TLRs eventually resolve danger-induced inflammation via transcriptional inhibition of S100B. Thus, the spatiotemporal regulation of TLRs and RAGE by S100B provides evidence for an evolving braking circuit in infection whereby an endogenous danger protects against pathogen–induced inflammation and a pathogen–sensing mechanism resolves danger–induced inflammation.
Inflammation results from recognition of invading microorganisms through pathogen–associated molecular patterns (PAMPs) and from reaction to tissue damage–associated molecular patterns (DAMPs). Despite the identification of specific signaling pathways negatively regulating responses to PAMPs or DAMPs, the unexpected convergence of molecular pathways responsible for recognition of either one raised the question of whether and how the host discriminates between the two distinct molecular patterns. Here we reveal a previously unknown mechanism by which the danger molecule S100B integrates pathogen– and danger–sensing pathways to restrain inflammation in Aspergillus fumigatus infection. By disclosing protective mechanisms that ensure prompt control of the pathogen and inflammation, our results may help to explain why humans inhale hundreds of Aspergillus conidia without adverse consequences.
Chronic inflammation is strongly associated with approximately 1/5th of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With regards to extraintestinal manifestations such as lymphoma, however, more suitable models are required to further investigate the complex and heterogeneous mechanisms that may be at play.
Recently, studies have been reported indicating that daily aspirin treatment for a period of 5 years or longer has a significant protective effect against death by colorectal carcinoma (as has previously been shown) and also against death by other solid cancers, both gastrointestinal and otherwise. These studies have reignited interest in the possibility of using nonsteroidal anti-inflammatory drugs for cancer prevention and the possibility that the numerous recent studies identifying the molecular mechanisms of the link between inflammation and cancer may allow the identification of better drugs for cancer prevention. Cancer often originates in tissues that are chronically inflamed, either in response to infections or noninfectious inflammation. Innate inflammation receptors, proinflammatory soluble factors, and inflammation-induced transcription factors have been identified that provide an understanding of some of the molecular pathways underlying the link between inflammation and cancer. However, the important role of the innate inflammatory pathways in host defense against pathogens and tissue damage as well as the maintenance of tissue integrity and homeostasis means that additional careful studies will be needed to identify anti-inflammatory interventions with the beneficial effect of tumor prevention without unacceptable toxic side effects.