Mediators and receptors in the resolution of inflammation: drug targeting opportunities

The active resolution of inflammation is recognized as offering new opportunities to generate novel anti-inflammatory agents. The emerging appreciation of the importance of active resolution in regulation of inflammation also creates an imperative to examine developing and existing agents for their potential to influence these pathways. This themed issue of the British Journal of Pharmacology contains papers that discuss the roles of annexin-1, lipoxins and related lipid products of fish oils as well as other mechanisms involved in active resolution and their receptor targets.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Histamine H1 receptor knockout mice exhibit impaired spatial memory in the eight-arm radial maze

Background and purpose:

In the mammalian brain, histaminergic neurotransmission is mediated by the postsynaptic histamine H₁ and H₂ receptors and the presynaptic H₃ autoreceptor, which also acts as a heteroreceptor. The H₁ receptor has been implicated in spatial learning and memory formation. However, pharmacological and lesion studies have revealed conflicting results. To examine the involvement of histamine H₁ receptor in spatial reference and working memory formation, H₁ receptor knockout mice (KO) were tested in the eight-arm radial maze. Previously, we found that the H₁ receptor-KO mice showed reduced emotionality when confronted with spatial novelty. As it is known that emotions can have an impact on spatial learning and memory performance, we also evaluated H₁ receptor-KO mice in terms of emotional behaviour in the light–dark box.

Experimental approach:

Mice lacking the H₁ receptor and wild-type mice (WT) were tested for spatial reference and working memory in an eight-arm radial maze with three arms baited and one trial per day. Emotional behaviour was measured using the light–dark test.

Key results:

The H₁ receptor-KO mice showed impaired spatial reference and working memory in the radial maze task. No significant differences between H₁ receptor-KO and WT mice were observed in the light–dark test.

Conclusions and implications:

The spatial memory deficits of the H₁ receptor-KO mice might be due to the reported changes in cholinergic neurochemical parameters in the frontal cortex and the CA1 subregion of the hippocampus, to impaired synaptic plasticity in the hippocampus, and/or to a dysfunctional brain reward/reinforcement system.     

Regional radiotherapy versus an axillary lymph node dissection after lumpectomy: a safe alternative for an axillary lymph node dissection in a clinically uninvolved axilla in breast cancer. A case control study with 10 years follow up

Background

To correlate the metabolic changes with size changes for tumor response by concomitant PET-CT evaluation of lung cancers after radiotherapy.

Methods

36 patients were studied pre- and post-radiotherapy with¹⁸FDG PET-CT scans at a median interval of 71 days. All of the patients were followed clinically and radiographically after a mean period of 342 days for assessment of local control or failure rates. Change in size (sum of maximum orthogonal diameters) was correlated with that of maximum standard uptake value (SUV) of the primary lung cancer before and after conventional radiotherapy.

Results

There was a significant reduction in both SUV and size of the primary cancer after radiotherapy (p < 0.00005). Among the 20 surviving patients, the sensitivity, specificity, and accuracy using PET (SUV) were 94%, 50%, 90% respectively and the corresponding values using and CT (size criteria) were 67%, 50%, and 65% respectively. The metabolic change (SUV) was highly correlated with the change in size by a quadratic function. In addition, the mean percentage metabolic change was significantly larger than that of size change (62.3 ± 32.7% vs 47.1 ± 26.1% respectively, p = 0.03)

Conclusion

Correlating and incorporating metabolic change by PET into size change by concomitant CT is more sensitive in assessing therapeutic response than CT alone.     

Inhibition of inducible nitric oxide synthase gene expression and nitric oxide synthesis in vascular smooth muscle cells by granulocyte-colony stimulating factor in vitro.

Clinical and experimental evidence suggests that granulocyte-colony stimulating factor (G-CSF) acts as an anti-inflammatory modulator with beneficial effects in severe inflammatory diseases, e.g., sepsis and septic shock. Excessive production of nitric oxide (NO) is regarded as a potent mediator of the vascular changes leading to systemic hypotension that occurs during sepsis. Therefore, the aim of the present study was to investigate the influence of G-CSF on inducible nitric oxide synthase (iNOS) gene expression and NO synthesis in vascular smooth muscle cells (VSMC). Qualitative and quantitative analyses of iNOS cDNA revealed that G-CSF significantly reduced interferon-gamma/lipopolysaccharide (IFN-gamma/LPS) dependent iNOS gene expression (P < 0.05) following 6, 18, 24, and 48 h incubation periods. In addition, the co-application of G-CSF resulted in a decreased IFN-gamma/LPS mediated iNOS protein generation as detected by immunoblotting methods after 24 and 48 h. Measurement of the stable NO metabolites showed a significant reduction of nitrite/nitrate concentrations following co-incubation of VSMC with G-CSF + IFN-gamma/LPS (242.57 +/- 10.73 nmol NO2-/NO3-/mg cell protein, n = 8) as compared to IFN-gamma/LPS treatment (306.20 +/- 19.26 nmol NO2-/NO3-/mg cell protein, n = 8, P < 0.05) following a 24-h incubation protocol. This inhibitory effect of G-CSF was still present after a 48 h incubation period (G-CSF + IFN-gamma/LPS: 319.56 +/- 6.26 nmol NO2-/NO3-/mg cell protein; IFN-gamma/LPS: 489.20 +/- 27.15 nmol NO2-/NO3-/mg cell protein (P < 0.05), n = 8, respectively). The present findings suggest that inhibition of iNOS gene expression and NO generation in VSMC might be one of the protective anti-inflammatory effects of G-CSF during sepsis.     

Risk factors for development of dehydration in young children with acute watery diarrhoea: a case-control study

In a case-control study to understand the risk factors for development of life-threatening dehydration, a total of 379 children comprising 243 cases (moderate or severe dehydration) and 136 controls (non or mild dehydration) up to 2 years of age suffering from acute watery diarrhoea were studied. By univariate analysis, the presence of vibrios in stool, withdrawal of breast feeding during diarrhoea, not giving fluids, including oral rehydration solution (ORS), during diarrhoea, frequent purging (> 8/ day), vomiting (> 2/day) and undernutrition were identified as risk factors. However, by multivariate analysis after controlling for confounders, withdrawal of breast feeding during diarrhoea (odds ratio (OR) = 6.8, p < 0.00001) and not giving ORS during diarrhoea (OR = 2.1, p < 0.006) were identified as significant risk factors. The confounding variables which also contributed significantly to increasing the risk were age (≤ 12 months; OR = 2.7, p = 0.001), frequent purging (> 8/day; OR = 4.1, p < 0.00001), vomiting (> 2/day; OR = 2.4, p = 0.001) and severe undernutrition (%median <60 weight-for-age of Indian Academy of Paediatrics classification; OR = 3.1, p = 0.001). We feel that these findings will be useful for Global and National Diarrhoeal Diseases Control Programmes for formulating intervention strategies for preventing death due to diarrhoeal dehydration.     

COBALAMIN DEFICIENCY and SMALL BOWEL BACTERIAL OVERGROWTH: A COMMON ASSOCIATION

Background  Bacterial overgrowth may cause cobalamin deficiency through competition for dietary cobalamin in the small intestine. The objective of this study was to prospectively determine the prevalence of small bowel bacterial overgrowth in patients with documented cobalamin deficiency in a tertiary referral centre.
Methods  Patients identified with cobalamin deficiency underwent diagnostic investigations including: Endoscopy (with gastric antrum, gastric body and duodenal biopsies and duodenal aspirate), ¹⁴C-D-Xylose breath test, intrinsic factor antibody, anti-endomysial antibody and red cell folate level. 'Definite' small bowel bacterial overgrowth was defined as either a positive ¹⁴C-D-Xylose breath test or > 100 000 CFU/mL of culture of duodenal aspirate. 'Suspected' small bowel bacterial overgrowth was defined as an elevated red cell folate in the absence of supplemental folate therapy.
Results  Over a 2-year period, 62 patients with cobalamin deficiency were identified, of whom, 26 (42%) had 'definite' small bowel bacterial overgrowth, whilst a further nine (15%) had 'suspected' small bowel bacterial overgrowth. Nineteen (31%) had pernicious anaemia, and no cause for cobalamin deficiency could be found in eight (13%) patients. The diagnosis found in the remaining patients included coeliac disease (4), Crohn's Disease (1), gastric resection (2), vegan (2), homozygotes of the MTHFR gene (C677T) mutation (2), and one had enteropathy associated with common variable immunodeficiency (CVID). 'Definite' small bowel bacterial overgrowth was found to coexist with nine of the 19 cases of pernicious anaemia, two coeliac subjects, one CVID enteropathy and one patient with the MTHFR gene mutation.
Conclusion  Small bowel bacterial overgrowth is commonly associated with cobalamin deficiency.     

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