Unscheduled apoptosis during acute inflammatory lung injury

Apoptosis is a mode of cell death currently thought to occur in the absence of inflammation. In contrast, inflammation follows unscheduled events such as acute tissue injury which results in necrosis, not apoptosis. We examined the relevance of this paradigm in three distinct models of acute lung injury; hyperoxia, oleic acid, and bacterial pneumonia. In every case, it was found that apoptosis is actually a prominent component of the acute and inflammatory phase of injury. Moreover, using strains of mice that are differentially sensitive to hyperoxic lung injury we observed that the percent of apoptotic cells was well correlated with the severity of lung injury. These observations suggest that apoptosis may be one of the biological consequences during acute injury and the failure to remove these apoptotic cells may also contribute to the inflammatory response.     

E-prostanoid-3 receptors mediate the proinflammatory actions of prostaglandin E2 in acute cutaneous inflammation

PGs are derived from arachidonic acid by PG-endoperoxide synthase (PTGS)-1 and PTGS2. Although enhanced levels of PGs are present during acute and chronic inflammation, a functional role for prostanoids in inflammation has not been clearly defined. Using a series of genetically engineered mice, we find that PTGS1 has the capacity to induce acute inflammation, but PTGS2 has negligible effects on the initiation of this response. Furthermore, we show that the contribution of PTGS1 is mediated by PGE(2) acting through the E-prostanoid (EP)3 receptor. Moreover, in the absence of EP3 receptors, inflammation is markedly attenuated, and the addition of nonsteroidal anti-inflammatory agents does not further impair the response. These studies demonstrate that PGE(2) promotes acute inflammation by activating EP3 receptors and suggest that EP3 receptors may be useful targets for anti-inflammatory therapy.     

The dynamics of acute inflammation

When the body is infected, it mounts an acute inflammatory response to rid itself of the pathogens and restore health. Uncontrolled acute inflammation due to infection is defined clinically as sepsis and can culminate in organ failure and death. We consider a three-dimensional ordinary differential equation model of inflammation consisting of a pathogen, and two inflammatory mediators. The model reproduces the healthy outcome and diverse negative outcomes, depending on initial conditions and parameters. We analyze the various bifurcations between the different outcomes when key parameters are changed and suggest various therapeutic strategies. We suggest that the clinical condition of sepsis can arise from several distinct physiological states, each of which requires a different treatment approach.     

Gender, obesity and repeated elevation of C-reactive protein: data from the CARDIA cohort

C-reactive Protein (CRP) measurements above 10 mg/L have been conventionally treated as acute inflammation and excluded from epidemiologic studies of chronic inflammation. However, recent evidence suggest that such CRP elevations can be seen even with chronic inflammation. The authors assessed 3,300 participants in The Coronary Artery Risk Development in Young Adults study, who had two or more CRP measurements between 1992/3 and 2005/6 to a) investigate characteristics associated with repeated CRP elevation above 10 mg/L; b) identify subgroups at high risk of repeated elevation; and c) investigate the effect of different CRP thresholds on the probability of an elevation being one-time rather than repeated. 225 participants (6.8%) had one-time and 103 (3.1%) had repeated CRP elevation above 10 mg/L. Repeated elevation was associated with obesity, female gender, low income, and sex hormone use. The probability of an elevation above 10 mg/L being one-time rather than repeated was lowest (51%) in women with body mass index above 31 kg/m(2), compared to 82% in others. These findings suggest that CRP elevations above 10 mg/L in obese women are likely to be from chronic rather than acute inflammation, and that CRP thresholds above 10 mg/L may be warranted to distinguish acute from chronic inflammation in obese women.     

Chlamydia pneumoniae Infection in Mice Induces Chronic Lung Inflammation,iBALT Formation,and Fibrosis

Chlamydia pneumoniae (CP) lung infection can induce chronic lung inflammation and is associated with not only acute asthma but also COPD exacerbations. However, in mouse models of CP infection, most studies have investigated specifically the acute phase of the infection and not the longer-term chronic changes in the lungs. We infected C57BL/6 mice with 5×10⁵ CP intratracheally and monitored inflammation, cellular infiltrates and cytokine levels over time to investigate the chronic inflammatory lung changes. While bacteria numbers declined by day 28, macrophage numbers remained high through day 35. Immune cell clusters were detected as early as day 14 and persisted through day 35, and stained positive for B, T, and follicular dendritic cells, indicating these clusters were inducible bronchus associated lymphoid tissues (iBALTs). Classically activated inflammatory M1 macrophages were the predominant subtype early on while alternatively activated M2 macrophages increased later during infection. Adoptive transfer of M1 but not M2 macrophages intratracheally 1 week after infection resulted in greater lung inflammation, severe fibrosis, and increased numbers of iBALTS 35 days after infection. In summary, we show that CP lung infection in mice induces chronic inflammatory changes including iBALT formations as well as fibrosis. These observations suggest that the M1 macrophages, which are part of the normal response to clear acute C. pneumoniae lung infection, result in an enhanced acute response when present in excess numbers, with greater inflammation, tissue injury, and severe fibrosis.     

Absence of stearoyl-CoA desaturase-1 does not promote DSS-induced acute colitis

Absence of stearoyl-CoA desaturase-1 (SCD1) in mice leads to chronic inflammation of the skin and increased susceptibility to atherosclerosis, while also increasing plasma inflammatory markers. A recent report suggested that SCD1 deficiency also increases disease severity in a mouse model of inflammatory bowel disease, induced by dextran sulfate sodium (DSS). However, SCD1-deficient mice are known to consume increased amounts of water, which would also be expected to increase the intake of DSS-treated water. The aim of this study was to determine the effect of SCD1 deficiency on DSS-induced acute colitis with DSS dosing adjusted to account for genotype differences in fluid consumption. Wild-type controls were treated with 3.5% DSS for 5 days to induce moderately severe colitis, while the concentration of DSS given to SCD1-deficient mice was lowered to 2.5% to control for increased fluid consumption. Colonic inflammation was assessed by clinical and histological scoring. Although SCD1-deficient mice consumed a total intake of DSS that was greater than that of wild-type controls, colonic inflammation, colon length and fecal blood were not altered by SCD1-deficiency in DSS-induced colitis, while diarrhea and total weight loss were modestly improved. Despite SCD1 deficiency leading to chronic inflammation of the skin and increased susceptibility to atherosclerosis, it does not accelerate inflammation in the DSS-induced model of acute colitis when DSS intake is controlled. These observations suggest that SCD1 deficiency does not play a significant role in colonic inflammation in this model.     

A role for acute-phase serum amyloid A and high-density lipoprotein in oxidative stress,endothelial dysfunction and atherosclerosis

Abstract

The acute-phase protein serum amyloid A (SAA) is a clinically useful marker of inflammation and associates strongly with increased risk of cardiovascular events. Chronically elevated SAA concentrations may contribute to physiological processes that lead to atherosclerosis, including endothelial dysfunction, an early and predictive event in the development of cardiovascular disease. Accumulating data suggest that SAA can be a direct mediator in the development and progression of atherogenesis and atherothrombosis. SAA may affect key events underlying acute coronary syndromes, including cholesterol transport, contribute to endothelial dysfunction, promote thrombosis, and enhance leukocyte trafficking and activation. This review summarizes the evidence supporting a role for SAA as a potential regulator of inflammation and endothelial dysfunction, which underlie the adverse outcomes that complicate coronary artery disease. The findings suggest that novel therapeutic strategies to reduce SAA levels and/or oppose the actions of SAA may have beneficial effects in patients with coronary artery disease.     

Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction

The purinergic receptor P2Y2 binds ATP to control chemotaxis of myeloid cells, and global P2Y2 receptor knockout mice are protected in models of acute inflammation. Chronic inflammation mediated by macrophages and other immune cells in adipose tissue contributes to the development of insulin resistance. Here, we investigate whether mice lacking P2Y2 receptors on myeloid cells are protected against acute and chronic inflammation. Wild-type mice were transplanted with either wild-type or P2Y2 receptor null bone marrow and treated with a sublethal dose of endotoxin as a model of acute inflammation, or fed a high-fat diet to induce obesity and insulin resistance as a model of chronic inflammation. P2Y2^?/? chimeric mice were protected against acute inflammation. However, high-fat diet feeding induced comparable inflammation and insulin resistance in both WT and P2Y2^?/? chimeric mice. Of note, confocal microscopy revealed significantly fewer crown-like structures, assemblies of macrophages around adipocytes, in P2Y2^?/? chimeric mice compared to WT chimeric mice. We conclude that P2Y2 receptors on myeloid cells are important in mediating acute inflammation but are dispensable for the development of whole body insulin resistance in diet-induced obese mice.     

Critical Role of Aquaporins in Interleukin 1β (IL-1β)-induced Inflammation

Rapid changes in cell volume characterize macrophage activation, but the role of water channels in inflammation remains unclear. We show here that, in vitro, aquaporin (AQP) blockade or deficiency results in reduced IL-1β release by macrophages activated with a variety of NLRP3 activators. Inhibition of AQP specifically during the regulatory volume decrease process is sufficient to limit IL-1β release by macrophages through the NLRP3 inflammasome axis. The immune-related activity of AQP was confirmed in vivo in a model of acute lung inflammation induced by crystals. AQP1 deficiency is associated with a marked reduction of both lung IL-1β release and neutrophilic inflammation. We conclude that AQP-mediated water transport in macrophages constitutes a general danger signal required for NLRP3-related inflammation. Our findings reveal a new function of AQP in the inflammatory process and suggest a novel therapeutic target for anti-inflammatory therapy.     

Prolactin is involved in the systemic inflammatory response in myocardial infarction

Prolactin may contribute to an atherogenic phenotype. Furthermore, previous studies have shown that prolactin levels increase in situations of acute stress and inflammation. We therefore aimed to investigate the relationship between prolactin, acute stress and inflammation in patients with myocardial infarction. We performed a case-control study in 40 patients with myocardial infarction and 39 controls, aged 41-84 years. Blood for assessment of prolactin and high sensitive C-reactive protein (hsCRP) was drawn at inclusion, that is, during the acute phase of the event, and 2-3 weeks later. Unexpectedly, prolactin levels at inclusion did not differ between cases and controls (7.0 ng/ml and 6.0 ng/ml, respectively, p=0.28). 2-3 weeks later prolactin levels in cases had not decreased. However, univariate regression analysis indicated that hsCRP is associated with prolactin levels (regression coefficient β 0.11; [95% CI 0.01; 0.21]; p=0.03) in cases during the acute phase of myocardial infarction. Our findings may suggest that prolactin is involved in the systemic inflammatory response, which takes place during myocardial infarction; however, this association may not be strong enough to induce higher prolactin levels in patients with myocardial infarction.     

Elevated serum leptin concentrations induced by experimental acute inflammation

Leptin is a pleiotropic hormone that regulates body weight and energy expenditure. Recent findings suggest that leptin may be involved in acute and/or chronic inflammation, however only limited results are available describing the effects of in vivo models of acute inflammation on leptin secretion. The aim of this study was to evaluate serum leptin levels in response to two well-established models of acute inflammation in rats: carrageenan rat paw induced oedema and carrageenan induced pleurisy. Our results clearly show that leptin levels rise in rats in which both oedema and pleurisy were induced. Serum leptin levels in carrageenan induced paw oedema were 3.86+/-0.16 microg/L in comparison to 1.83+/-0.17 microg/L of control animals (p<0.001). A similar result was observed in carrageenan induced pleurisy animals in which leptin levels were 4.87+/-0.27 microg/L in comparison to 2.19+/-0.16 microg/L of control animals (p<0.001). The increase in leptin levels induced following carrageenan-induced pleurisy appears to be dependent on adrenal function and it is markedly blunted in adrenalectomized rats. Leptin levels in carrageenan induced pleurisy, carried out on adrenalectomized rats, were lower than intact inflamed animals, suggesting a possible involvement of endogenous glucocorticoids. In summary the results here presented show that: a) an elevated plasma leptin concentration was induced during experimental models of inflammation b) this increase is mediated to a large extent by glucocorticoids. In conclusion, acute experimental models of inflammation are associated with changes in circulating leptin suggesting a possible involvement of this hormone in the anorexia/cachexia that is frequently associated with inflammatory processes. Furthermore, our data indicate the existence of a feedback loop among glucocorticoids and leptin which might contribute to the immune response to lace the inflammatory process.     

Acute ozone-induced change in airway permeability: role of infiltrating leukocytes.

The role of infiltrating polymorphonuclear leukocytes (PMNs) in acute lung injury and inflammation is still controversial. In inbred mice, acute ozone (O3) exposure induces airway inflammation that is characterized by a maximal influx of lavageable PMNs 6 h after exposure and a maximal increase in lung permeability 24 h after O3. We tested the hypothesis that O3-induced change in airway epithelial permeability of O3-susceptible C57BL/6J mice is due to infiltrating PMNs. Male mice (6-8 wk) were treated with a nonsteroidal anti-inflammatory drug (indomethacin), a chemotactic inhibitor (colchicine), or an immunosuppressant (cyclophosphamide) to deplete or inhibit PMNs from infiltrating the airways. After drug or vehicle treatment, mice were exposed for 3 h to 2 ppm O3 or filtered air, and pulmonary inflammation was assessed by inflammatory cell counts and total protein content (a marker of airway permeability) in bronchoalveolar lavage (BAL) fluid. Filtered air exposure did not affect the parameters of pulmonary inflammation at any time after exposure. Compared with vehicle controls, each of the drug treatments resulted in significant reduction of PMN influx 6 and 24 h after O3. However, total BAL protein content was not attenuated significantly by the three treatments at either 6 or 24 h postexposure. Results of these experiments suggest that the influx of PMNs and the change in total BAL protein are not mutually dependent events in this model and suggest that infiltrating PMNs do not play a major role in acute O3-induced changes in permeability of the murine lung.     

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

Patients with inflammatory bowel disease (IBD) suffer from body weight loss, malnutrition, and several other metabolic alterations affecting their quality of life. The aim of this study was to investigate the metabolic changes that may occur during acute and chronic colonic inflammation induced by dextran sulfate sodium (DSS) in mice. Clinical symptoms and inflammatory markers revealed the presence of an ongoing inflammatory response in the DSS-treated mice. Mice with acute inflammation had decreased body weight, respiratory exchange ratios (RER), food intake, and body fat content. Mice with chronic inflammation had decreased nutrient uptake, body fat content, locomotor activity, metabolic rates, and bone mineral density. Despite this, the body weight, food and water intake, lean mass, and RER of these mice returned to values similar to those in healthy controls. Thus, murine experimental colitis is associated with significant metabolic alterations similar to IBD patients. Our data show that the metabolic responses during acute and chronic inflammation are different, although the metabolic rate is reduced in both phases. These observations suggest compensatory metabolic alterations in chronic colitis resulting in a healthy appearance despite gross colon pathology.     

Catecholamines induce IL-10 release in patients suffering from acute myocardial infarction by transactivating its promoter in monocytic but not in T-cells

The anti-inflammatory cytokine IL-10 is up-regulated in response to TNF- suggesting a control mechanism of inflammation. In addition, we recently found systemic IL-10 release in response to acute stress reactions in the absence of any systemic inflammation. In vitro and in vivo studies in experimental models suggest that catecholamines induce IL-10 release via a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) dependent pathway. Here we studied patients for plasma IL-10 after acute myocardial infarction, a very stressful event without significant signs of systemic inflammation. In fact, the activation of the sympathetic system initiated by cardiac infarction was accompanied by a temporary systemic release of IL-10. Catecholamine induced IL-10 may be released by different cells. Recently, we demonstrated that catecholamines directly stimulate the IL-10 promoter/enhancer via a cAMP/PKA pathway in monocytic cells. A cAMP responsive element (CRE) was identified as major target. Here we show that there is no influence of catecholamines on the IL-10 promoter activity in T-cells. In contrast to monocytic cells, in T-cells cAMP-induced PKA-dependent phosphorylation of the CRE-binding protein 1 (CREB-1) seems to play a marginal role in IL-10 induction, which was reflected by a low cAMP-dependent IL-10-promoter/enhancer stimulation in reporter gene assays. Thus, catecholamines are directly involved in the regulation of IL-10 expression in monocytic but not in T-cells after acute stressful conditions.     

The deficiency of macrophage erythropoietin signaling contributes to delayed acute inflammation resolution in diet-induced obese mice

Obesity has been linked with altered acute inflammation resolution which contributes to obesity-related clinical complications; however, the mechanisms that contribute to obesity-related unresolved inflammation are not fully known. Here we demonstrated that the deficiency of macrophage erythropoietin (EPO) signaling contributed to delayed acute inflammation resolution in diet-induced obese mice. In zymosan-induced acute peritonitis, in line with the delayed resolution of inflammation, the induction of macrophage EPO signaling was significantly reduced in obese mice relative to normal mice. Exogenous EPO induced macrophage EPO signaling and promoted acute inflammation resolution in obese mice. Efferocytosis of apoptotic cells by macrophages which is central in inflammation resolution was impaired in obese mice and restored by exogenous EPO. Mechanistically, macrophage peroxisome proliferator-activated receptor-γ (PPARγ) was greatly reduced in obese mice and EPO increased macrophage PPARγ to promote efferocytosis in obese mice. Together, our results identify an important mechanism underlying aberrant acute inflammation resolution in obesity, with important implications for regulating unresolved acute inflammation and normalizing macrophage defects in obese and diabetic individuals.     

1,3,7-trimethylxanthine (caffeine) may exacerbate acute inflammatory liver injury by weakening the physiological immunosuppressive mechanism

The genetic elimination of A2A adenosine receptors (A2AR) was shown to disengage the critical immunosuppressive mechanism and cause the dramatic exacerbation of acute inflammatory tissue damage by T cells and myeloid cells. This prompted the evaluation of the proinflammatory vs the anti-inflammatory effects of the widely consumed behavioral drug caffeine, as the psychoactive effects of caffeine are mediated largely by its antagonistic action on A2AR in the brain. Because caffeine has other biochemical targets besides A2AR, it was important to test whether the consumption of caffeine during an acute inflammation episode would lead to the exacerbation of immune-mediated tissue damage. We examined acute and chronic treatment with caffeine for its effects on acute liver inflammation. It is shown that caffeine at lower doses (10 and 20 mg/kg) strongly exacerbated acute liver damage and increased levels of proinflammatory cytokines. Because caffeine did not enhance liver damage in A2AR-deficient mice, we suggest that the potentiation of liver inflammation was mediated by interference with the A2AR-mediated tissue-protecting mechanism. In contrast, a high dose of caffeine (100 mg/kg) completely blocked both liver damage and proinflammatory cytokine responses through an A2AR-independent mechanism. Furthermore, caffeine administration exacerbated liver damage even when mice consumed caffeine chronically, although the extent of exacerbation was less than in "naive" mice that did not consume caffeine before. This study suggests an unappreciated "man-made" immunological pathogenesis whereby consumption of the food-, beverage-, and medication-derived adenosine receptor antagonists may modify an individual's inflammatory status and lead to excessive organ damage during acute inflammation.     

Skeletal muscle PGC-1α is required for maintaining an acute LPS-induced TNFα response

Many lifestyle-related diseases are associated with low-grade inflammation and peroxisome proliferator activated receptor γ coactivator (PGC)-1α has been suggested to be protective against low-grade inflammation. However, whether these anti-inflammatory properties affect acute inflammation is not known. The aim of the present study was therefore to investigate the role of muscle PGC-1α in acute inflammation. Quadriceps muscles were removed from 10-week old whole body PGC-1α knockout (KO), muscle specific PGC-1α KO (MKO) and muscle-specific PGC-1α overexpression mice (TG), 2 hours after an intraperitoneal injection of either 0.8 μg LPS/g body weight or saline. Basal TNFα mRNA content was lower in skeletal muscle of whole body PGC-1α KO mice and in accordance TG mice showed increased TNFα mRNA and protein level relative to WT, indicating a possible PGC-1α mediated regulation of TNFα. Basal p65 phosphorylation was increased in TG mice possibly explaining the elevated TNFα expression in these mice. Systemically, TG mice had reduced basal plasma TNFα levels compared with WT suggesting a protective effect against systemic low-grade inflammation in these animals. While TG mice reached similar TNFα levels as WT and showed more marked induction in plasma TNFα than WT after LPS injection, MKO PGC-1α mice had a reduced plasma TNFα and skeletal muscle TNFα mRNA response to LPS. In conclusion, the present findings suggest that PGC-1α enhances basal TNFα expression in skeletal muscle and indicate that PGC-1α does not exert anti-inflammatory effects during acute inflammation. Lack of skeletal muscle PGC-1α seems however to impair the acute TNFα response, which may reflect a phenotype more susceptible to infections as also observed in type 2 diabetes patients.