Although the mechanism of aspirin-induced asthma and rhinitis is unknown, it has been suggested that adverse nasal and bronchial reactions are caused by an increased production of lipoxygenase products. In examining this hypothesis we have measured the release of peptide leukotrienes (PeptLTs), 15-HETE, and prostaglandins in nasal fluids obtained by nasal lavages after instillation of acetylsalycilic acid (ASA) and placebo (saline). Ten ASA-sensitive asthmatics, 10 ASA-insensitive asthmatics, and seven healthy subjects were challenged in a double-blind study with normal saline and 12 mg of ASA. Twelve mg were administered based on the results of a previous study that showed that this dose caused minor to moderate symptoms in ASA-sensitive patients. PeptLTs, LTB4, 15-HETE, PGE2, PGF2 alpha, and PGD2 were measured by radioimmunoassay methods. Significant levels of PeptLTs were detected in sensitive asthmatic patients 60 min after nasal challenge. This change was associated with a significant increase in symptoms. No increase in PeptLTs levels were found, however, in either insensitive patients or healthy subjects. Inhibition of PGE2 and PGF2 alpha release was detected in the three groups after ASA administration. ASA also inhibited PGD2 release in insensitive asthmatic patients but not in both sensitive patients and healthy subjects. These results suggest that an abnormal release of PeptLTs in ASA-sensitive asthmatic patients contributes to nasal and bronchial adverse reactions. The lack of effects on PGD2 release suggests that mast cells from ASA-insensitive patients are more sensitive to ASA than those from sensitive asthmatic patients and healthy subjects.

Inflammation is a response that has evolved over millions of years to become an extremely complex process. This complexity reflects the host's need to deal effectively with a wide variety of potentially injurious agents, as well as the need to incorporate an adequate set of checks and balances. An inappropriately checked response, which occurs rarely, results in disease, either acute or chronic. However, in most instances, inflammation is a beneficial response, essential for survival. Inflammation comprises an extensive network of cellular interactions implemented by an overwhelming number of molecules. One category of signal includes soluble products, such as neuropeptide, lipid mediators, cytokines and growth factors, most of which can be produced by inflammatory/haemopoietic cells. However, resident structural cells can also produce many of these products and, on this basis only, fibroblasts, epithelial, endothelial and smooth muscle cells should be considered as active contributors to the regulation of the inflammatory response. Extracellular matrix (ECM) proteins comprise another category of signals. Whilst the most recognized activities of these proteins are those concerned with providing structural tissue integrity, it is clear that they also have powerful inductive effects. Indeed, ECM proteins can influence the shape, movement and state of activation of inflammatory cells in the tissue. Recent evidence indicates that these signals may also play substantial roles in homing of inflammatory cells to certain sites and in the handling of a number of cytokines and growth factors. In so far as fibroblasts are the main producers of ECM proteins, these new data establish an indirect but important role for fibroblasts in the regulation of the inflammatory response.

Nitric oxide (NO) plays an important regulatory role in airway function and seems to be implicated in the pathophysiology of several airway diseases. To better understand the involvement of NO in the upper airways, we examined the presence of nitric oxide synthase (NOS) activity in human nasal mucosa and nasal polyp tissues. Nasal mucosa was obtained from seven patients undergoing septoplasty, and nasal polyps came from nine patients following polypectomy. NOS activity was quantified in tissue homogenates using the citrulline release assay and localized in tissue sections using reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. The results showed that nasal polyps (n = 9) contained higher levels of total NOS activity (mean +/- SD 5.94 +/- 5.71, range 1.29-18.0 pmol.min-1.mg protein) than nasal mucosa tissues (n = 7) (0.28 +/- 0.22, range 0.01-0.57 pmol.min-1.mg protein). In addition, nasal polyps mainly contained inducible NOS activity (4.67 +/- 4.57, range 1.23-15.5 pmol.min-1.mg protein) whereas in nasal mucosa all NOS activity detected was in constitutive form. In both cases, NOS activity was localized in the epithelial cells. Since NO synthase is induced in inflamed upper airways, we conclude that NO may be an important inflammatory mediator in the respiratory system and that the epithelium may be a source of NO production in the human upper airways.

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Cadmium (Cd) was the third heavy metal investigated in the European collaborative research project on the development and validation of new markers of nephrotoxicity. Fifty workers exposed to Cd and 50 control workers were examined. After application of selection criteria 37 workers (mean age 43) exposed to Cd for an average of 11-3 years; and 43 age matched referents were retained for final analysis. The average concentrations of Cd in blood (Cd-B) and urine (Cd-U) of exposed workers were 5-5 pg Cd/l and 5-4 pg Cd/g creatinine respectively. By contrast with lead and mercury, Cd had a broad spectrum of effects on the kidney, producing significant alterations in amounts of almost all potential indicators of nephrotoxicity that were measured in urine-namely, low and high molecular weight proteins, kidney derived antigens or enzymes, prostanoids, and various other biochemical indices such as glycosaminoglycans and sialic acid. An increase in i2-microglobulin and a decrease of sialic acid

The present study has been carried out in the framework of a collaborative research project on the development of new markers of nephrotoxicity. A battery of more than 20 potential indicators of renal changes has been applied to 50 workers exposed to lead (Pb) and 50 control subjects. After application of selection criteria 41 exposed and 41 control workers were eventually retained for the final statistical analysis. The average blood Pb concentration of exposed workers was 480 micrograms/l and their mean duration of exposure was 14 years. The battery of tests included parameters capable of detecting functional deficits (for example, urinary proteins of low or high molecular weight), biochemical alterations (for example, urinary eicosanoids, glycosaminoglycans, sialic acid) or cell damage (for example, urinary tubular antigens or enzymes) at different sites of the nephron or the kidney. The most outstanding effect found in workers exposed to Pb was an interference with the renal synthesis of eicosanoids, resulting in lower urinary excretion of 6-keto-PGF1 alpha and an enhanced excretion of thromboxane (TXB2). The health significance of these biochemical alterations, detectable at low exposure to Pb is unknown. As they were not associated with any sign of renal dysfunction, they may represent reversible biochemical effects or only contribute to the degradation of the renal function from the onset of clinical Pb nephropathy. The urinary excretion of some tubular antigens was also positively associated with duration of exposure to Pb. Another effect of Pb that might deserve further study is a significant increase in urinary sialic acid concentration.

BackgroundPhosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression.MethodCells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry.ResultsJAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells.ConclusionsTargeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0436-2) contains supplementary material, which is available to authorized users.

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