Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK-STAT signaling in macrophages by perturbing lipid raft structures.

Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163high CD206high tumor-associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signaling, mirrored by an impaired transcriptional response to interferons and IL-6 in monocyte-derived macrophages by AA. This inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA-mediated interference with STAT1 phosphorylation. Inhibition of interferon-triggered STAT1 phosphorylation by AA was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.

α-Linolenic Acid-Rich Diet Influences Microbiota Composition and Villus Morphology of the Mouse Small Intestine.

α-Linolenic acid (ALA) is well-known for its anti-inflammatory activity. In contrast, the influence of an ALA-rich diet on intestinal microbiota composition and its impact on small intestine morphology are not fully understood. In the current study, we kept adult C57BL/6J mice for 4 weeks on an ALA-rich or control diet. Characterization of the microbial composition of the small intestine revealed that the ALA diet was associated with an enrichment in Prevotella and Parabacteroides. In contrast, taxa belonging to the Firmicutes phylum, including Lactobacillus, Clostridium cluster XIVa, Lachnospiraceae and Streptococcus, had significantly lower abundance compared to control diet. Metagenome prediction indicated an enrichment in functional pathways such as bacterial secretion system in the ALA group, whereas the two-component system and ALA metabolism pathways were downregulated. We also observed increased levels of ALA and its metabolites eicosapentanoic and docosahexanoic acid, but reduced levels of arachidonic acid in the intestinal tissue of ALA-fed mice. Furthermore, intestinal morphology in the ALA group was characterized by elongated villus structures with increased counts of epithelial cells and reduced epithelial proliferation rate. Interestingly, the ALA diet reduced relative goblet and Paneth cell counts. Of note, high-fat Western-type diet feeding resulted in a comparable adaptation of the small intestine. Collectively, our study demonstrates the impact of ALA on the gut microbiome and reveals the nutritional regulation of gut morphology.

Urinary uromodulin independently predicts end-stage renal disease and rapid kidney function decline in a cohort of chronic kidney disease patients.

Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline (i.e., within 1 year) in chronic kidney disease (CKD) are rare but urgently needed to plan treatment. This study describes the association and predictive value of urinary uromodulin (uUMOD) for rapid progression of CKD.We assessed uUMOD, demographic/treatment parameters, estimated glomerular filtration rate (eGFR), and proteinuria in 230 CKD patients stage I-V. ESRD and 25% decline of eGFR was documented at the end of follow-up period and used as a composite endpoint. Association between logarithmic uUMOD and eGFR/proteinuria was calculated using linear regression analysis, adjusting for age, gender, and body mass index. We performed multivariable Cox proportional hazard regression analysis to evaluate the association of uUMOD with the composite endpoint. Therefore, patients were categorized into quartiles. The predictive value of uUMOD for the above outcomes was assessed using receiver-operating characteristic (ROC) curve analysis.Follow-up was 57.3 ±â€Š18.7 weeks, baseline age was 60 (18;92) years, and eGFR was 38 (6;156) mL/min/1.73 m. Forty-seven (20.4%) patients reached the composite endpoint. uUMOD concentrations were directly associated with eGFR and inversely associated with proteinuria (ß = 0.554 and ß = -0.429, P < .001). In multivariable Cox regression analysis, the first 2 quartiles of uUMOD concentrations had a hazard ratio (HR) of 3.589 [95% confidence interval (95% CI) 1.002-12.992] and 5.409 (95% CI 1.444-20.269), respectively, in comparison to patients of the highest quartile (≥11.45 µg/mL) for the composite endpoint. In ROC-analysis, uUMOD predicted the composite endpoint with good sensitivity (74.6%) and specificity (76.6%) at an optimal cut-off at 3.5 µg/mL and area under the curve of 0.786 (95% CI 0.712-0.860, P < .001).uUMOD was independently associated with ESRD/rapid loss of eGFR. It might serve as a robust predictor of rapid kidney function decline and help to better schedule arrangements for future treatment.

Cell type-selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment.

The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl-LPA species are strongly elevated in ascites versus plasma and are associated with short relapse-free survival. Data derived from transcriptome and secretome analyses of primary ascite-derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2 ) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor-associated macrophages play an essential role as main producers of PLA2 G7 and autotaxin. The latter conclusion is consistent with mass spectrometry-based metabolomic analyses of conditioned medium from ascites cells, which showed that tumor-associated macrophages, but not tumor cells, are able to produce 20:4 acyl-LPA in lipid-free medium. Furthermore, our transcriptomic data revealed that LPA receptor (LPAR) genes are expressed in a clearly cell type-selective manner: While tumor cells express predominantly LPAR1-3, macrophages and T cells also express LPAR5 and LPAR6 at high levels, pointing to cell type-selective LPA signaling pathways. RNA profiling identified cytokines linked to cell motility and migration as the most conspicuous class of LPA-induced genes in macrophages, suggesting that LPA exerts protumorigenic properties at least in part via the tumor secretome.

Serum uromodulin-a marker of kidney function and renal parenchymal integrity.

Background: An ELISA to analyse uromodulin in human serum (sUmod) was developed, validated and tested for clinical applications. Methods: We assessed sUmod, a very stable antigen, in controls, patients with chronic kidney disease (CKD) stages 1-5, persons with autoimmune kidney diseases and recipients of a renal allograft by ELISA. Results: Median sUmod in 190 blood donors was 207 ng/mL (women: men, median 230 versus 188 ng/mL, P = 0.006). sUmod levels in 443 children were 193 ng/mL (median). sUmod was correlated with cystatin C (rs = -0.862), creatinine (rs = -0.802), blood urea nitrogen (BUN) (rs = -0.645) and estimated glomerular filtration rate (eGFR)-cystatin C (rs = 0.862). sUmod was lower in systemic lupus erythematosus-nephritis (median 101 ng/mL), phospholipase-A2 receptor- positive glomerulonephritis (median 83 ng/mL) and anti-glomerular basement membrane positive pulmorenal syndromes (median 37 ng/mL). Declining sUmod concentrations paralleled the loss of kidney function in 165 patients with CKD stages 1-5 with prominent changes in sUmod within the 'creatinine blind range' (71-106 µmol/L). Receiver-operating characteristic analysis between non-CKD and CKD-1 was superior for sUmod (AUC 0.90) compared with eGFR (AUC 0.39), cystatin C (AUC 0.39) and creatinine (AUC 0.27). sUmod rapidly recovered from 0 to 62 ng/mL (median) after renal transplantation in cases with immediate graft function and remained low in delayed graft function (21 ng/mL, median; day 5-9: relative risk 1.5-2.9, odds ratio 1.5-6.4). Immunogold labelling disclosed that Umod is transferred within cytoplasmic vesicles to both the apical and basolateral plasma membrane. Umod revealed a disturbed intracellular location in kidney injury. Conclusions: We conclude that sUmod is a novel sensitive kidney-specific biomarker linked to the structural integrity of the distal nephron and to renal function.

A new missense mutation in UMOD gene leads to severely reduced serum uromodulin concentrations - A tool for the diagnosis of uromodulin-associated kidney disease.

BACKGROUND: Uromodulin-associated Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD) belongs to a group of autosomal dominant inherited diseases caused by mutations in the UMOD gene, which codes for uromodulin, a protein exclusively expressed in renal tubular cells of the ascending limb of the loop of Henle. The diagnosis is hampered by non-specific clinical, laboratory and histological findings. In this study, we evaluated serum uromodulin as diagnostic marker for ADTKD-UMOD in a family with a novel mutation in UMOD. METHODS: We investigated a family with five members suffering from chronic kidney disease of unknown origin (CKD) and three healthy members using whole exome sequencing. Serum uromodulin was measured by ELISA. The uromodulin concentration of each CKD family member was compared to reference CKD groups with similar eGFR and to non-CKD individuals in case of the healthy family members, respectively. RESULTS: Whole exome sequencing revealed novel missense mutation c.457T>G, p.(Cys153Gly) in UMOD. Serum uromodulin concentration was lower in all affected patients compared to all patients of the reference CKD groups, while healthy family members showed normal values comparable to those of the non-CKD reference group. CONCLUSIONS: The mutation detected in our family leads to severely reduced serum uromodulin concentrations, distinguishing these patients clearly from CKD patients with comparable eGFR. Therefore, serum uromodulin could serve as a simple, new diagnostic marker to identify patients with ADTKD-UMOD.

Determination of red blood cell fatty acid profiles: Rapid and high-confident analysis by chemical ionization-gas chromatography-tandem mass spectrometry.

Cellular fatty acid (FA) profiles have been acknowledged as biomarkers in various human diseases. Nevertheless, common FA analysis by gas chromatography mass spectrometry (GC-MS) requires long analysis time. Hence, there is a need for feasible methods for high throughput analysis in clinical studies. FA was extracted from red blood cells (RBC) and derivatized to fatty acid methyl esters (FAME). A method using gas chromatography tandem mass spectrometry (GC-MS/MS) with ammonia-induced chemical ionization (CI) was developed for the analysis of FA profiles in human RBC. We compared this method with classical single GC-MS using electron impact ionization (EI). The FA profiles of 703 RBC samples were determined by GC-MS/MS. In contrast to EI ammonia-induced CI resulted in adequate amounts of molecular ions for further fragmentation of FAME. Specific fragments for confident quantification and fragmentation were determined for 45 FA. The GC-MS/MS method has a total run time of 9min compared to typical analysis times of up to 60min in conventional GC-MS. Intra and inter assay variations were <10% for all FA analyzed. Analysis of RBC FA composition revealed an age-dependent increase of the omega-3 eicosapentaenoic and docosahexaenoic acid, and a decline of the omega-6 linoleic acid with a corresponding rise of the omega-3 index. The combination of ammonia-induced CI and tandem mass spectrometry after GC separation allows for high-throughput, robust and confident analysis of FA profiles in the clinical laboratory.

Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients.

Uromodulin, released from tubular cells of the ascending limb into the blood, may be associated with kidney function. This work studies the relevance of plasma uromodulin as a biomarker for kidney function in an observational cohort of chronic kidney disease (CKD) patients and subjects without CKD (CKD stage 0). It should be further evaluated if uromodulin allows the identification of early CKD stages.Plasma uromodulin, serum creatinine, cystatin C, blood-urea-nitrogen (BUN) concentrations, and estimated glomerular filtration rate (eGFR CKD-EPIcrea-cystatin) were assessed in 426 individuals of whom 71 were CKD stage 0 and 355 had CKD. Besides descriptive statistics, univariate correlations between uromodulin and biomarkers/eGFR were calculated using Pearson-correlation coefficient. Multiple linear regression modeling was applied to establish the association between uromodulin and eGFR adjusted for demographic parameters and pharmacologic treatment. Receiver-operating-characteristic (ROC) analysis adjusted for demographic parameters was performed to test if uromodulin allows differentiation of subjects with CKD stage 0 and CKD stage I.Mean uromodulin plasma levels were 85.7 ±â€Š60.5 ng/mL for all CKD stages combined. Uromodulin was correlated with all biomarkers/eGFR in univariate analysis (eGFR: r = 0.80, creatinine: r = -0.76, BUN: r = -0.72, and cystatin C: r = -0.79). Multiple linear regression modeling showed significant association between uromodulin and eGFR (coefficient estimate ß = 0.696, 95% confidence interval [CI] 0.603-0.719, P < 0.001). In ROC analysis uromodulin was the only parameter that significantly improved a model containing demographic parameters to differentiate between CKD 0° and I° (area under the curve [AUC] 0.831, 95% CI 0.746-0.915, P = 0.008) compared to creatinine, cystatin C, BUN, and eGFR (AUC for creatinine: 0.722, P = 0.056, cystatin C: 0.668, P = 0.418, BUN: 0.653, P = 0.811, and eGFR: 0.634, P = 0.823).Plasma uromodulin serves as a robust biomarker for kidney function and uniquely allows the identification of early stages of CKD. As a marker of tubular secretion it might represent remaining nephron mass and therefore intrinsic "kidney function" rather than just glomerular filtration, the latter only being of limited value to represent kidney function as a whole. It therefore gives substantial information on the renal situation in addition to glomerular filtration and potentially solves the problem of creatinine-blind range of CKD, in which kidney impairment often remains undetected.

ω-3 fatty acids contribute to the asthma-protective effect of unprocessed cow's milk.

BACKGROUND: Living on a farm has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow's milk obtained directly from a farm. However, this phenomenon has never been shown in a longitudinal design, and the responsible milk components are still unknown. OBJECTIVES: We sought to assess the asthma-protective effect of unprocessed cow's milk consumption in a birth cohort and to determine whether the differences in the fatty acid (FA) composition of unprocessed farm milk and industrially processed milk contributed to this effect. METHODS: The Protection Against Allergy-Study in Rural Environments (PASTURE) study followed 1133 children living in rural areas in 5 European countries from birth to age 6 years. In 934 children milk consumption was assessed by using yearly questionnaires, and samples of the "usually" consumed milk and serum samples of the children were collected at age 4 years. Doctor-diagnosed asthma was parent reported at age 6 years. In a nested case-control study of 35 asthmatic and 49 nonasthmatic children, 42 FAs were quantified in milk samples. RESULTS: The risk of asthma at 6 years of age was reduced by previous consumption of unprocessed farm milk compared with shop milk (adjusted odds ratio for consumption at 4 years, 0.26; 95% CI, 0.10-0.67). Part of the effect was explained by the higher fat content of farm milk, particularly the higher levels of ω-3 polyunsaturated FAs (adjusted odds ratio, 0.29; 95% CI, 0.11-0.81). CONCLUSION: Continuous farm milk consumption in childhood protects against asthma at school age partially by means of higher intake of ω-3 polyunsaturated FAs, which are precursors of anti-inflammatory mediators.

Development and clinical application of a LC-MS/MS method for simultaneous determination of various tyrosine kinase inhibitors in human plasma.

BACKGROUND: Increasing numbers of tyrosine kinase inhibitors (TKIs) were studied and approved for therapy of malignancies and other diseases. The aim of this study was to develop and validate a specific, simple and rapid quantification method for various TKIs in human plasma. METHODS: A simultaneous test for six TKIs (erlotinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib) was developed using liquid chromatography tandem mass spectrometry in a multiple reaction monitoring mode. After protein precipitation the specimens were applied to the HPLC system and separated using a gradient of acetonitrile containing 1% formic acid with 10 mM ammoniumformiate on an analytic RP-C18 column. RESULTS: The calibration range was 10-1000 ng/mL for sunitinib and 50-5000 ng/mL for the other TKIs with coefficients of determination ≥0.99 for all analytes. The intra- and inter day coefficients of variation were ≤15% and the chromatographic run time was 12 min. Plasma specimens were stable for measurement for at least 1 week at 4°C. Clinical applications of the assay are exemplarily discussed. CONCLUSIONS: This novel high-throughput method is suitable for specific simultaneous determination of different TKIs in routine clinical practice.

Nerve growth factor induces type III collagen production in chronic allergic airway inflammation.

BACKGROUND: Excessive extracellular matrix deposition occurs as a result of repetitive injury-repair cycles and plays a central role in the pathogenesis of chronic inflammatory diseases, such as allergic asthma. The molecular mechanism leading to aberrant collagen deposition is not fully understood. OBJECTIVE: We sought to test the hypothesis that increased nerve growth factor (NGF) production contributes to collagen deposition in the airways during chronic allergic airway inflammation. METHODS: Antibody-blocking experiments were performed in an in vivo model for chronic allergic airway inflammation (allergic asthma), which is accompanied by matrix deposition in the subepithelial compartment of the airways, to study the profibrotic effect of NGF. The signaling pathways were delineated with in vivo and in vitro studies in primary lung fibroblasts. RESULTS: Functional blocking of NGF in chronically affected mice markedly prevented subepithelial fibrosis. Transgenic overexpression of NGF in murine airways resulted in altered airway wall morphology with increased peribronchial collagen deposition and impaired lung physiology in the absence of inflammation. NGF exerted a direct effect on collagen expression in murine lung fibroblasts, which was mainly mediated through the activation of the receptor tropomyosin-related kinase A. NGF-induced collagen expression was dependent on downstream activation of p38 mitogen-activated protein kinase independent of the TGF-ß1/mothers against decapentaplegic homolog (SMAD) pathway. CONCLUSION: The results of this study demonstrate that NGF exerts profibrotic activities in the airways by inducing type III collagen production in fibroblasts independently of TGF-ß1.

Development and validation of a combined method for the biomonitoring of omega-3/-6 fatty acids and conjugated linoleic acids in different matrices from human and nutritional sources.

BACKGROUND: During the last decade, the contribution of omega-3 and -6 long chain-polyunsaturated fatty acids (LC-PUFA) and conjugated linoleic acids (CLA) to the prevention and development of many inflammatory and cardiovascular diseases has been of growing interest. In order to investigate the etiology of these diseases, rapid, combined and comparable methods are invaluable for monitoring both the intake and the incorporation of these fatty acids (FA). METHODS: The fatty acid methyl esters (FAME) were analyzed using a gas chromatography/flame ionization detector (GC-FID) system and quantified with an internal standard (C18:0 iso). RESULTS: An effective and rapid protocol for sample preparation and the analysis of FAME was developed and validated. The comparison of different extraction methods showed that the Hara and Radin method gave the best results for serum and erythrocyte membranes. Excellent mean within-day and day-to-day precisions for serum, erythrocytes and cow's milk LC-PUFAs demonstrated the high reproducibility of the method. Recovery rates for FAMEs in serum and milk were close to 100%. In addition, high mean method linearity (R(2)) (>0.99) was shown for serum, erythrocytes and cow's milk. The sensitivity for FA achieved by GC analysis was acceptable. CONCLUSION: With the newly adapted protocols, combined and rapid analyses of up to 46 FAMEs, including CLAs and omega-3/-6 LC-PUFAs, can be conducted with high reliability and reproducibility using serum, erythrocyte membranes or cow's milk. This provides a novel tool that can be easily implemented in epidemiological studies or clinical diagnostics.

Airway epithelial cells produce neurotrophins and promote the survival of eosinophils during allergic airway inflammation.

BACKGROUND: Eosinophil-epithelial cell interactions make a major contribution to asthmatic airway inflammation. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and other members of the neurotrophin family, originally defined as a class of neuronal growth factors, are now recognized to support the survival and activation of immune cells. Neurotrophin levels are increased in bronchoalveolar lavage fluid during allergic asthma. OBJECTIVE: We sought to investigate the role of neurotrophins as inflammatory mediators in eosinophil-epithelial cell interactions during the allergic immune response. METHODS: Neurotrophin expression in the lung was investigated by means of immunohistochemistry and ELISA in a mouse model of chronic experimental asthma. Coculture experiments were performed with airway epithelial cells and bronchoalveolar lavage fluid eosinophils. RESULTS: Neurotrophin levels increased continuously during chronic allergic airway inflammation, and airway epithelial cells were the major source of NGF and BDNF within the inflamed lung. Epithelial neurotrophin production was upregulated by IL-1beta, TNF-alpha, and T(H)2 cytokines. Lung eosinophils expressed the BDNF and NGF receptors tropomyosin-related kinase (Trk) A and TrkB, and coculture with airway epithelial cells resulted in enhanced epithelial neurotrophin production, as well as in prolonged survival of eosinophils. Eosinophil survival was completely abolished in the presence of the neurotrophin receptor Trk antagonist K252a. CONCLUSION: During allergic inflammation, airway epithelial cells express increased amounts of NGF and BDNF that promote the survival of tissue eosinophils. Controlling epithelial neurotrophin production might be an important therapeutic target to prevent allergic airway eosinophilia. CLINICAL IMPLICATIONS: Attenuating the release of inflammatory mediators from the activated airway epithelium will become an important strategy to disrupt the pathogenesis of chronic allergic asthma.

Neurotrophins in allergic diseases: from neuronal growth factors to intercellular signaling molecules.

Understanding the complex pathophysiology of allergic diseases has been a main challenge of clinical and experimental research for many years. It is well known that the allergic inflammation triggers neuronal dysfunction and structural changes in the diseased tissues such as the airways or the skin. Recent evidence has emerged that the inflammatory response is also controlled by resident tissue cells such as neurons and structural cells. Therefore, signaling molecules that mediate inflammatory interactions among immune, neuronal, and structural cells are becoming a focus of allergy research. Neurotrophins, a family of homologous growth factors initially discovered in the nervous system, display such bidirectional signaling. The expression of neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), is highly upregulated during allergic inflammation. Neurons, structural cells, and invading immune cells were now identified not only as sources but also as targets of neurotrophins within the inflamed tissue. In this review, we provide an actual overview of the role of neurotrophins in the pathobiology of allergic diseases. We discuss recent findings in human and animal studies such as the regulation of neurotrophin expression during allergic inflammation and the effect of neurotrophins on the development and magnitude of allergic reactions.

Neurotrophins and asthma: novel insight into neuroimmune interaction.

There is increasing evidence that neuronal dysfunction and dysregulation contribute to the pathogenesis of allergic asthma. Many functional aspects of peripheral neurons strongly depend on the activity of neurotrophins, a family of mediators originally defined by their neuronal growth activity. More recently, it has been discovered that neurotrophins (eg, nerve growth factor, brain-derived neurotrophin factor, and neurotrophin 3) have profound activities on various immune cells involved in the pathogenesis of allergic disease. Furthermore, immune cells themselves can produce neurotrophins under certain conditions, and the levels of neurotrophins, as well as neurotrophic activities, are strongly upregulated in allergic conditions. Animal data demonstrate that a number of pathomechanisms controlling allergic diseases are directly related to neurotrophin function, including the development of airway hyperresponsiveness. These findings now lead to a much better understanding concerning the regulatory loop between immunologic and neurogenic dysregulation. In this review we will provide an overview of how neurotrophins connect the pathobiology of airway inflammation and hyperresponsiveness, which are the hallmarks of allergic asthma.

A role for brain-derived neurotrophic factor in B cell development.

In the present study, we demonstrated a significant reduction of B lymphocytes in the blood, spleen and bone marrow of BDNF deficient mice. The observed developmental block in bone marrow B cell development was linked specifically to the Pre-BII stage. B lymphocytes express the BDNF receptors p75NTR and TrkB(gp95), while no BDNF expression was found. However, a strong BDNF expression was demonstrated in bone marrow stromal cells. An increase of intracellular free calcium [Ca2+]i in B lymphocytes after BDNF application confirms a direct responsiveness of B lymphocytes to BDNF. In conclusion, these results suggest a role of BDNF for normal B lymphocyte development through paracrine effects in the bone marrow.

Neurotrophins in clinical diagnostics: pathophysiology and laboratory investigation.

There is now growing evidence that a number of multifunctional signaling molecules, originally discovered as signal molecules in specific cells, exert their effects in various other tissue compartments. Neurotrophins, a class of homologues growth factors initially discovered to promote neuronal growth and survival, display such a dual activity and contribute to the development of a variety of non-neuronal tissues. Nowadays, several examples of essential non-neuronal functions played by neurotrophins and of variations of neurotrophin expression that accompany these processes can be presented. As will be shown, neurotrophins are found in many body tissues produced by a variety of non-neuronal cell types such as immune cells, adipocytes, endothelia, epithelia, fibroblasts, keratinocytes and endocrine cells. Assuming a general role as growth and survival factors, changes in neurotrophin expression may reflect physiological or pathological processes, such as activation, proliferation or repair followed by injury in the tissues. Neurotrophins were also present in the systemic blood circulation and variations in blood concentrations indicate vascular as well as peripheral production. In this review, we will discuss changes in local and systemic neurotrophin concentrations as well as their known pathophysiological relationship in various inflammatory and non-inflammatory disorders. Beside the nervous system, these will include diseases of the airways, skin and joints as well as systemic autoimmune diseases. Furthermore, new aspects of neurotrophin actions in maintenance of body energy balance and in reproductive endocrinology will be presented.

The role of neurotrophins in bronchial asthma: contribution of the pan-neurotrophin receptor p75.

Allergic bronchial asthma is characterized by chronic inflammation of the airways, development of airway hyperreactivity and recurrent reversible airway obstruction. Target and effector cells responsible for airway hyperresponsiveness and airway obstruction include sensory and motor neurons as well as epithelial and smooth muscle cells. Although it is well established that the inflammatory process is controlled by T-helper-2 (Th2) cells, the mechanisms by which immune cells interact with neurons, epithelial cells or smooth muscle cells still remain uncertain. Due to growing evidence for extensive communication between neurons and immune cells, the mechanisms of this neuroimmune crosstalk in lung and airways of asthmatic patients are becoming the focus of asthma research. Neurotrophins represent molecules potentially responsible for regulating and controlling the crosstalk between the immune and peripheral nervous system. They are constitutively expressed by resident lung cells and produced in increasing concentrations by immune cells invading the airways under pathological conditions. Neurotrophins modify the functional activity of sensory and motor neurons, leading to enhanced and altered neuropeptide and tachykinin production. These effects are defined as neuronal plasticity. The consequences are the development of neurogenic inflammation.

Neurotrophins in inflammatory lung diseases: modulators of cell differentiation and neuroimmune interactions.

Chronic inflammatory lung diseases represent a group of severe diseases with increasing prevalence as well as epidemiological importance. Inflammatory lung diseases could result from allergic or infectious genesis. There is growing evidence that the immune and nervous system are closely related not only in physiological but also in pathological reactions in the lung. Extensive communications between neurons and immune cells are responsible for the magnitude of airway inflammation and the development of airway hyperreactivity, a consequence of neuronal dysregulation. Neurotrophins are molecules regulating and controlling this crosstalk between the immune and peripheral nervous system (PNS) during inflammatory lung diseases. They are constitutively expressed by resident lung cells and produced in increasing quantities by immune cells invading the airways under inflammatory conditions. They act as activation, differentiation and survival factors for cells of both the immune and nervous system. This article will review the most recent data of neurotrophin signaling in the normal and inflamed lung and as yet unexplored, roles of neurotrophins in the complex communication within the neuroimmune network.

Control of nerve growth and plasticity.

Respiratory function is under close control of the autonomic nervous system. Recent data indicate that dysfunction and dysregulation of both the non-adrenergic non-cholinergic (NANC) and cholinergic system contribute to the pathogenesis of chronic inflammatory lung disease such as bronchial asthma. Sensory neurons of the NANC system in particular exhibit a great degree of plasticity. It has been shown that neurotrophins play an important role in modulating sensory innervation in such conditions. In addition, several inflammatory mediators also contribute to sensory nerve plasticity in this context. Cholinergic nerves represent the dominant broncho-constrictory pathway and the role of the muscarinic M(2) receptor has been recently characterized in this regard. In summary, recent data provide new insights into dysfunction and dysregulation of the autonomic nervous system as observed in chronic inflammatory lung disease.