Low-grade Systemic Inflammatory Response Research Articles

Inflammatory responses and obesity: Nutrition as an epigenetic modulator

The onset of inflammation takes place in a human body due to an injury or infection during which the tissue becomes inflamed/reddened, swollen, hot, and painful. Basically, it is a collection of host defenses that occurs during an injury and infection in which the white blood cells protect the body from infection from bacteria, fungi, parasites, or viruses. Innate immunity provides the first challenging defense against the diverse foreign harmful invaders, while adaptive immunity, also known as acquired immunity, utilizes specialized immune cells and antibodies, which provide a counterattack and destroy these diverse foreign invaders. Moreover, they can prevent infections/diseases in the future by recognizing those invaders and providing a new immune response. However, when an immune system responds too aggressively to an infection, a condition termed a cytokine storm takes place, which may lead to multi-organ failure and even death. Inflammatory response in advancing age and obesity is intricately associated. Obesity has been identified as a low-grade systemic inflammatory response. Particularly, elevated levels of serum C-reactive protein, interleukin-6, tumor necrosis factor-α, and leptin, well characterized biomarkers of inflammation, are observed predominantly in obese individuals.

Mid-gestation low-dose LPS administration results in female-specific excessive weight gain upon a western style diet in mouse offspring

Gestational complications, including preeclampsia and gestational diabetes, have long-term adverse consequences for offspring’s metabolic and cardiovascular health. A low-grade systemic inflammatory response is likely mediating this. Here, we examine the consequences of LPS-induced gestational inflammation on offspring’s health in adulthood. LPS was administered to pregnant C57Bl/6J mice on gestational day 10.5. Maternal plasma metabolomics showed oxidative stress, remaining for at least 5 days after LPS administration, likely mediating the consequences for the offspring. From weaning on, all offspring was fed a control diet; from 12 to 24 weeks of age, half of the offspring received a western-style diet (WSD). The combination of LPS-exposure and WSD resulted in hyperphagia and increased body weight and body fat mass in the female offspring. This was accompanied by changes in glucose tolerance, leptin and insulin levels and gene expression in liver and adipose tissue. In the hypothalamus, expression of genes involved in food intake regulation was slightly changed. We speculate that altered food intake behaviour is a result of dysregulation of hypothalamic signalling. Our results add to understanding of how maternal inflammation can mediate long-term health consequences for the offspring. This is relevant to many gestational complications with a pro-inflammatory reaction in place.

Systemic administration of pentoxifylline attenuates the development of hypertension in renovascular hypertensive rats

There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 μg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.

Incides of C-Reactive Protein, Tumor Necrosis Factor-α, Adiponectin, Leptin and Resistin in the Blood of Patients Suffering from Chronic Pancreatitis and Type 2 Diabetes Mellitus.

Studying the significance of the immune response to damage and adipokine levels is urgent regarding the development of both chronic pancreatitis and type 2 diabetes mellitus. Our objective was to study the indices of tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), adiponectin, leptin, and resistin as links for triggering the mechanisms of development and progression of the low-grade chronic systemic inflammatory response in chronic pancreatitis (CP) patients with type 2 diabetes mellitus (T2DM). The study groups consisted of 87 patients: 47 patients with isolated CP (group I), 40 with CP combined with T2DM (group II), and 41 practically healthy persons. It has been established that in patients with isolated CP, the TNF-α concentration showed a reliable 1.57-fold (p <0.05) increase compared to practically healthy persons (PHP) and a 1.32-fold increase in patients who also had T2DM (p<0.05). CP patients with type 2 diabetes mellitus had the highest CRP indices (5.5-fold, p <0.05. TNF-α and C-reactive protein indices were higher in patients with chronic pancreatitis and T2DM than those with isolated chronic pancreatitis, characterizing the persistence of chronic systemic inflammation in case of the combined clinical course of these diseases.

Lifestyle Factors that can Induce an Independent and Persistent Low-Grade Systemic Inflammatory Response: A Wholistic Approach

Subclinical inflammation was first shown in numerous chronic medical illnesses and in the early 1900s, activation of immune-inflammatory pathways was initially observed in a lifestyle-related disorder such as depression. A chronic mild inflammatory state is also a key feature of obesity as well as insulin resistance and other metabolic diseases. This particular form of immune process has given rise to the concept of “metaflammation” (metabolically triggered inflammation) because it can target vital organs and tissues that are critical for the regulation of metabolism, and ultimately disrupt systemic homoeostasis with detrimental health effects. However, accumulating evidence demonstrates a link between metaflammation and a number of lifestyle factors. Lifestyle variables such as ultra-endurance exercise, physical inactivity, extremes of sleep duration, cigarette smoking, burnout, anxiety, and depression can activate multiple immune-inflammatory pathways. Therefore, this review of the literature that bears hallmarks of a systematic review investigates and presents published research data of these lifestyle factors that can induce an independent and persistent low-grade systemic inflammatory response, within the human body, evaluated through the measurement of various biomarkers.

Coronary artery disease concomitant with chronic obstructive pulmonary disease

Numerous epidemiologic studies have linked the presence of chronic obstructive pulmonary disease (COPD) to coronary artery disease (CAD). However, prevalence, pathological processes, clinical manifestations and therapy are still debated, as progress towards uncovering the link between these two disorders has been hindered by the complex nature of multimorbidity. Articles targeting CAD in patients with COPD were identified from the searches of MEDLINE and EMBASE databases in July 2013. Three authors reviewed available evidence, focusing on the latest development on disease prevalence, pathogenesis, clinical manifestations and therapeutic strategies. Both clinical trial and previous reviews have been included in this work. The most accredited hypothesis asserts that the main common risk factors, that is, cigarette smoke and ageing, elicit a chronic low-grade systemic inflammatory response, which affects both cardiovascular endothelial cells and airways/lung parenchyma. The development of CAD in patients with COPD potentiates the morbidity of COPD, leading to increased hospitalizations, mortality and health costs. Moreover, correct diagnosis is challenging and therapies are not clearly defined. Evidence from recently published articles highlights the importance of multimorbidity in patient management and future research. Moreover, many authors emphasize the importance of low-grade systemic inflammation as a common pathological mechanism and a possible future therapeutic target.

Reply to Balta et al.

We appreciate the observations made by Balta et al. [1] with regard to red cell distribution width (RDW) and lung cancer. With regard to time from blood sampling to analysis for RDW, a Beckman LH750 was used for all analyses. Correspondence with Beckman, with regard to their coulter counter, advises that, as all samples were analysed within 12 h of collection, no significant errors in RDW measurement will have occurred. Each analyser has different stability parameters and RDW is stable for up to 24 h post-collection when analysed with the LH750. With regard to disease state and RDW, we adjusted for cancer stage. However, tumour half-life was not available. We also adjusted for a number of medical conditions as listed by Balta et al.; however, we did not have liver function data available. Previous analysis has demonstrated that alcohol is a significant factor for in-hospital death, which we adjusted for [2]. Balta et al. quite rightly point out the confounding effect of haemoglobin on RDW values. We adjusted for this, as has been previously described via the use of multivariate regression [3]. With regard to the inflammatory status at the time of measurement, all patients were elective resections; however, we cannot rule out a low-grade systemic inflammatory response. Balta et al. are correct in pointing out the effect of inflammatory markers affecting the accuracy of prediction of clinical outcomes; however, the nature of our paper was identifying the effect of RDW on outcomes in thoracic surgery. We did not develop a model for risk prediction, and any such model would need to include inflammatory markers. Inflammatory markers that are cheap, clinically available and clinically significant remain to be defined and may vary from condition to condition. As Balta et al. point out, RDW seems to be a predictive factor in a number of disease states. We thus speculate that RDW is a marker of bone marrow function, in the same manner as creatinine, ejection fraction and forced expiratory volume in 1 s are for the kidneys, heart and lungs, respectively [2, 4]. We thank Balta et al. for their insightful comments.

Elevated high-sensitivity C-reactive protein in preterm infants with pulmonary colonization with Ureaplasma.

A link between pulmonary Ureaplasma spp. colonization in premature infants and bronchopulmonary dysplasia (BPD) exists and could possibly contribute to systemic inflammation. A prospective cohort study was performed from July 2006 to July 2007 where very low birth weight (VLBW) premature infants were screened at birth. Serum and tracheal aspirate samples were collected during the first 28 days of life that represented the early high-sensitivity C-reactive protein (hs-CRP) group, and follow-up samples obtained between 28-42 days of life were the late hs-CRP group. An Enzyme-linked immunosorbent assay (ELISA) for hs-CRP was performed on serum samples while tracheal aspirates underwent polymerase chain reaction (PCR) analysis for Ureaplasma spp. A total of 65 patients were screened. 30 patients completed full analysis, 15 died before early and late hs-CRP samples could be obtained, and 20 had incomplete data due to early discharge or transfer. There was no significant difference between all early and late hs-CRP group levels (mg/L), median [interquartile range] 1.019 [0.242, 5.844] vs. 0.773 [0.143, 8.954] (P=0.3958); however, there was a significant difference when comparing Ureaplasma spp. positivity vs. negativity between both groups, median 2.223 [0.398, 7.099] vs. 0.675 [0.219, 4.038] (P=0.0131) for the early group and median 2.335 [0.359, 14.91] vs. 0.2155 [0.122, 2.296] (P=0.03) for the late group, respectively. VLBW premature infants colonized with Ureaplasma spp. have an elevated hs-CRP, suggestive of a chronic low-grade systemic inflammatory response.

Reply to Balta et al.

We appreciate the observations made by Balta et al. [1] with regard to red cell distribution width (RDW) and lung cancer. With regard to time from blood sampling to analysis for RDW, a Beckman LH750 was used for all analyses. Correspondence with Beckman, with regard to their coulter counter, advises that, as all samples were analysed within 12 h of collection, no significant errors in RDW measurement will have occurred. Each analyser has different stability parameters and RDW is stable for up to 24 h post-collection when analysed with the LH750. With regard to disease state and RDW, we adjusted for cancer stage. However, tumour half-life was not available. We also adjusted for a number of medical conditions as listed by Balta et al.; however, we did not have liver function data available. Previous analysis has demonstrated that alcohol is a significant factor for in-hospital death, which we adjusted for [2]. Balta et al. quite rightly point out the confounding effect of haemoglobin on RDW values. We adjusted for this, as has been previously described via the use of multivariate regression [3]. With regard to the inflammatory status at the time of measurement, all patients were elective resections; however, we cannot rule out a low-grade systemic inflammatory response. Balta et al. are correct in pointing out the effect of inflammatory markers affecting the accuracy of prediction of clinical outcomes; however, the nature of our paper was identifying the effect of RDW on outcomes in thoracic surgery. We did not develop a model for risk prediction, and any such model would need to include inflammatory markers. Inflammatory markers that are cheap, clinically available and clinically significant remain to be defined and may vary from condition to condition. As Balta et al. point out, RDW seems to be a predictive factor in a number of disease states. We thus speculate that RDW is a marker of bone marrow function, in the same manner as creatinine, ejection fraction and forced expiratory volume in 1 s are for the kidneys, heart and lungs, respectively [2, 4]. We thank Balta et al. for their insightful comments.

Analysis of procalcitonin and CRP concentrations in serum of patients with chronic spontaneous urticaria

BackgroundOur previous findings showed the importance of analysing the peripheral markers of acute phase response (APR) activation, C-reactive protein (CRP) and IL-6 in the context of urticaria activity and severity. However, these biomarkers do not reliably differentiate between APR to infectious and the disease severity.AimIn order to investigate a possible association between the immune-inflammatory activation markers CRP and procalcitonin (PCT).MethodsSerum PCT and CRP concentrations were measured in patients with CU of varying severity as well as in healthy subjects.ResultsSerum PCT and CRP concentrations were significantly increased in more severe CU patients when compared to healthy controls and mild CU, and within the CU population there was a significant correlation between concentrations of PCT and CRP. Serum PCT concentrations remained within normal ranges in most CU patients and were only slightly elevated in some severe CU cases.ConclusionsPCT serum concentration may be only slightly elevated in some cases of severe CU. Upregulation of PCT synthesis accompanied by parallel changes in CRP concentration reflects a low-grade systemic inflammatory response in CU. PCT should be considered as a better marker than CRP to distinguish between APR to infection and an active non-specific urticarial inflammation.

Lutein: More than just a filter for blue light

Lutein is concentrated in the primate retina, where together with zeaxanthin it forms the macular pigment. Traditionally lutein is characterized by its blue light filtering and anti-oxidant properties. Eliminating lutein from the diet of experimental animals results in early degenerative signs in the retina while patients with an acquired condition of macular pigment loss (Macular Telangiectasia) show serious visual handicap indicating the importance of macular pigment. Whether lutein intake reduces the risk of age related macular degeneration (AMD) or cataract formation is currently a strong matter of debate and abundant research is carried out to unravel the biological properties of the lutein molecule. SR-B1 has recently been identified as a lutein binding protein in the retina and this same receptor plays a role in the selective uptake in the gut. In the blood lutein is transported via high-density lipoproteins (HDL). Genes controlling SR-B1 and HDL levels predispose to AMD which supports the involvement of cholesterol/lutein transport pathways. Apart from beneficial effects of lutein intake on various visual function tests, recent findings show that lutein can affect immune responses and inflammation. Lutein diminishes the expression of various ocular inflammation models including endotoxin induced uveitis, laser induced choroidal neovascularization, streptozotocin induced diabetes and experimental retinal ischemia and reperfusion. In vitro studies show that lutein suppresses NF kappa-B activation as well as the expression of iNOS and COX-2. Since AMD has features of a chronic low-grade systemic inflammatory response, attention to the exact role of lutein in this disease has shifted from a local effect in the eye towards a possible systemic anti-inflammatory function.

Conventional mechanical periodontal therapy - A pioneering and nontoxic experimental model for the study of acute human inflammatory response

In the past decade, the association of periodontal diseases with the development of systemic diseases has received increasing attention. A variety of recent hypothesis driven investigations have compiled various results showing that periodontal infection and subsequent direct oral-haematogenous spread of bacteria are implicated in the development of inflammation and various systemic diseases. Chronic periodontitis causes a low-grade systemic inflammatory response; its standard treatment, however, induces an acute inflammatory response. The aim of this study was to describe the systemic inflammatory reactions to an intensive periodontal treatment regimen.

The capacity of foodstuffs to induce innate immune activation of human monocytesin vitrois dependent on food content of stimulants of Toll-like receptors 2 and 4

The ingestion of fatty meals is associated with a transient, low-grade systemic inflammatory response in human subjects, involving the activation of circulating monocytes and the secretion of pro-inflammatory cytokines. However, it is not yet clear how different foodstuffs may promote inflammatory signalling. In a screen of forty filter-sterilised soluble extracts from common foodstuffs, seven were found to induce the secretion of TNF-α and IL-6 from human monocytes in vitro. To investigate what may differentiate inflammatory from non-inflammatory food extracts, stimulants of Toll-like receptor (TLR) 2 and TLR4 were quantified using human embryonic kidney-293 cells transfected with each TLR, and calibrated with defined bacterial lipopeptide (BLP) and lipopolysaccharide (LPS) standards. These assays revealed that while most foods contained undetectable levels of TLR2 or TLR4 stimulants, all TNF-α-inducing foods contained stimulants of either TLR2 (up to 1100ng BLP-equivalent/g) or TLR4 (up to 2700ng LPS-equivalent/g) in both the soluble and insoluble fractions. TLR stimulants were present mainly in meat products and processed foods, but were minimal or undetectable in fresh fruit and vegetables. The capacity of food extracts to induce TNF-α secretion in monocytes correlated with the content of both TLR2 (r 0·837) and TLR4 stimulants (r 0·748), and was completely abolished by specific inhibition of TLR2 and TLR4. LPS and BLP were found to be highly resistant to typical cooking times and temperatures, low pH and protease treatment. In conclusion, apparently unspoiled foodstuffs can contain large quantities of stimulants of TLR2 and TLR4, both of which may regulate their capacity to stimulate inflammatory signalling.

Microvascular Responses to Cardiovascular Risk Factors

Hypertension, hypercholesterolemia, diabetes, and obesity are among a growing list of conditions that have been designated as major risk factors for cardiovascular disease (CVD). While CVD risk factors are well known to enhance the development of atherosclerotic lesions in large arteries, there is also evidence that the structure and function of microscopic blood vessels can be profoundly altered by these conditions. The diverse responses of the microvasculature to CVD risk factors include oxidative stress, enhanced leukocyte- and platelet-endothelial cell adhesion, impaired endothelial barrier function, altered capillary proliferation, enhanced thrombosis, and vasomotor dysfunction. Emerging evidence indicates that a low-grade systemic inflammatory response that results from risk factor-induced cell activation and cell-cell interactions may underlie the phenotypic changes induced by risk factor exposure. A consequence of the altered microvascular phenotype and systemic inflammatory response is an enhanced vulnerability of tissues to the deleterious effects of secondary oxidative and inflammatory stresses, such as ischemia and reperfusion. Future efforts to develop therapies that prevent the harmful effects of risk factor-induced inflammation should focus on the microcirculation.

Effects of Dialysis Purity on Uremic Dyslipidemia

Dyslipidemia, a prominent feature of end-stage renal disease, is considered a risk factor for premature atherosclerosis in hemodialysis (HD) patients. Dyslipidemia is related to loss of kidney function as well as use of low-flux cellulosic dialyzer membranes, but the effects of dialysate purity are unknown. Forty-eight incident HD patients started high-flux polysulfone maintenance HD, either with conventional (potentially contaminated) or with on-line produced ultrapure dialysate. The quality of the dialysis fluid (CFU/mL, endotoxin concentration), markers of inflammation (C-reactive protein, Il-6), and parameters of the lipid profile and oxidative stress (oxidized low-density lipoprotein) were measured before initiation of HD, and after 6, 12 and 24 months on HD. Compared to baseline, treatment with conventional (mildly contaminated) dialysate significantly increased the uremic low-grade systemic inflammatory response syndrome (SIRS), augmented uremic dyslipidemia (triglycerides by +21%, and high-density lipoprotein (HDL) cholesterol by -10%) and enhanced oxidative stress. In contrast, the use of ultrapure dialysate significantly decreased uremia-associated SIRS, dyslipidemia (triglycerides -7% and HDL cholesterol +11%) and oxidative stress. Ultrapure dialysis fluid improves potential parameters of cardiovascular risk by decreasing inflammatory reactions, improving uremic dyslipidemia and lowering oxidative stress.

Obesity-induced hepatic hypoperfusion primes for hepatic dysfunction after resuscitated hemorrhagic shock

Obese patients (BMI>35) after blunt trauma are at increased risk compared to non-obese for organ dysfunction, prolonged hospital stay, infection, prolonged mechanical ventilation, and mortality. Obesity and non-alcoholic fatty liver disease (NAFLD) produce a low grade systemic inflammatory response syndrome (SIRS) with compromised hepatic blood flow, which increases with body mass index. We hypothesized that obesity further aggravates liver dysfunction by reduced hepatic perfusion following resuscitated hemorrhagic shock (HEM). Age-matched Zucker rats (Obese, 314-519 g & Lean, 211-280 g) were randomly assigned to 4 groups (n = 10-12/group): (1) Lean-Sham; (2) Lean, HEM, and resuscitation (HEM/RES); (3) Obese-Sham; and (4) Obese-HEM/RES. HEM was 40% of mean arterial pressure (MAP) for 60 min; RES was return of shed blood/5 min and 2 volumes of saline/25 min. Hepatic blood flow (HBF) using galactose clearance, liver enzymes and complete metabolic panel were measured over 4 h after completion of RES. Obese rats had increased MAP, heart rate, and fasting blood glucose and BUN concentrations compared to lean controls, required less blood withdrawal (mL/g) to maintain 40% MAP, and RES did not restore BL MAP. Obese rats had decreased HBF at BL and during HEM/RES, which persisted 4 h post RES. ALT and BUN were increased compared to Lean-HEM/RES at 4 h post-RES. These data suggest that obesity significantly contributes to trauma outcomes through compromised vascular control or through fat-induced sinusoidal compression to impair hepatic blood flow after HEM/RES resulting in a greater hepatic injury. The pro-inflammatory state of NAFLD seen in obesity appears to prime the liver for hepatic ischemia after resuscitated hemorrhagic shock, perhaps intensified by insidious and ongoing hepatic hypoperfusion established prior to the traumatic injury or shock.

Obesity, Inflammation, and the Potential Application of Pharmaconutrition

Obesity is an emerging problem worldwide. Hospitalized obese patients often have a worse outcome than patients of normal weight, particularly in the setting of trauma and critical care. Obesity creates a low-grade systemic inflammatory response syndrome (SIRS) that is similar (but on a much smaller scale) to gram-negative sepsis. This process involves up-regulation of systemic immunity, is characterized clinically by insulin resistance and the metabolic syndrome, and puts the patient at increased risk for organ failure, infectious morbidity, and mortality. Through lipotoxicity and cytokine dysregulation, obesity may act to prime the immune system, predisposing to an exaggerated subsequent immune response when a second clinical insult occurs (such as trauma, burns, or myocardial infarction). Specialized nutrition therapy for such patients currently consists of a hypocaloric, high-protein diet. However, this approach does not address the putative pathophysiologic mechanisms of inflammation and altered metabolism associated with obesity. A number of dietary agents such as arginine, fish oil, and carnitine may correct these problems at the molecular level. Pharmaconutrition formulas may provide exciting innovations for the nutrition therapy of the obese patient.

Systemic Effects of Smoking

Smoking is one of the major lifestyle factors influencing the health of human beings. Life-long cigarette smokers have a higher prevalence of common diseases such as atherosclerosis and COPD with significant systemic impact. The present review evaluates current knowledge concerning possible pathways through which cigarette smoking can affect human health, with special focus on extrapulmonary effects. Long-term smoke exposure can result in systemic oxidants-antioxidants imbalance as reflected by increased products of lipid peroxidation and depleted levels of antioxidants like vitamins A and C in plasma of smokers. A low-grade systemic inflammatory response is evident in smokers as confirmed by numerous population-based studies: elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, as well as increased counts of WBC have been reported. Furthermore, rheologic, coagulation and endothelial function markers like hematocrit, blood and/or plasma viscosity, fibrin d-dimer, circulating adhesion molecules (intracellular adhesion molecule-1, selectins), tissue plasminogen activator antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers. Although most of smoking-induced changes are reversible after quitting, some inflammatory mediators like CRP are still significantly raised in ex-smokers up to 10 to 20 years after quitting, suggesting ongoing low-grade inflammatory response persisting in former smokers. New longitudinal epidemiologic and genetic studies are required to evaluate the role of smoking itself and possible gene/environment interplay in initiation and development of smoking-induced common diseases affecting humans.

The systemic face of airway diseases: the role of C-reactive protein

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are highly prevalent diseases, constituting a major financial burden to society. Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities. Airflow limitation is the dominant physiological characteristic of both diseases. The airflow limitation in asthma must be reversible to establish a diagnosis, whereas in COPD the airflow limitation does not change markedly over periods of several months and the disease is characterised by a steady downhill course over time. Asthma usually commences in childhood, whereas COPD is generally diagnosed at an older age. Lung inflammation induced by different initiating factors is now recognised as an important characteristic in both diseases. The airway inflammation in asthma is characterised by an increase in eosinophils, lymphocytes (predominantly of the CD4+ type) and mast cells. In contrast, inflammation in COPD can be described by a predominance of lymphocytes, in particular CD8+ lymphocytes, and large numbers of neutrophils in the airway lumen. While achievement of asthma control and suppression of airway inflammation are considered as important management goals in asthma, particularly as a consequence of the effects of inhaled steroids in this disease process, the focus of research in COPD has moved from the typical pulmonary pathology of COPD to the role of numerous abnormalities outside the lung. At present, COPD is considered as a multicomponent disease, including skeletal muscle dysfunction and cachexia, as well as cardiovascular and osteoskeletal alterations. Particularly in order to explain the process of muscle wasting, the presence of a chronic low-grade systemic inflammatory response has been identified as one of the catabolic factors, although the precise role, as well as the intracellular pathways, remain to be defined 1. In this issue of the European Respiratory Journal (ERJ) , two clinical papers focus attention …

Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats.

This study examines the effects of malnutrition on IL-6 signaling pathways of rats fed 2% vs. 20% casein diets for 14 days. Effects of malnutrition on the abundance and IL-6-stimulated phosphorylation of signaling proteins in the JAK-STAT and MAP kinase pathways were examined in the liver. Changes of the acute-phase response as reflected by serum alpha(1)-acid glycoprotein (AG), TNF-alpha (TNF), and IL-1beta (IL-1) were compared in the two dietary groups at 0, 4, 8, 16, and 24 h after IL-6 administration. Under basal conditions, the abundance of the IL-6 receptor, gp130, JAK1, STAT1, and STAT3 proteins and levels of phosphorylation of ERK1/2 and p38 were significantly increased in the liver in the 2% casein group compared with the 20% casein group. With IL-6 stimulation, the increased phosphorylation per unit of protein of these signaling proteins was not different in the liver between the two groups. Before IL-6 stimulation, serum levels of TNF, IL-1, IL-6, and AG were significantly higher in the 2% casein group than in the 20% casein group. After bolus injection of IL-6, changes in IL-1 and AG were similar in the two dietary groups, although a slight decline in AG level was noted after 8 h of IL-6 administration in the 2% protein group. These data demonstrate that protein malnutrition produces changes in inflammation-related proteins characteristic of a low-grade systemic inflammatory response and, thus, can serve as an inflammatory stimulus. The capacity for response to IL-6 is preserved, suggesting adaptive preservation of acute-phase responsiveness during malnutrition.