Lennart Jansson

Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

BackgroundToll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen.Methods27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins.ResultsmRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season.ConclusionThe up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation.

Circulating monocytes from healthy individuals and COPD patients

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by incompletely reversible airflow obstruction associated with inflammation in which monocytes/macrophages are the predominant inflammatory cells. The only known genetic factor related to COPD is inherited PiZZ deficiency of α1-antitrypsin (AAT), an inhibitor of serine proteases.MethodsWe investigated the basal and LPS-stimulated release of pro-inflammatory molecules from blood monocytes isolated from age and gender matched healthy (n = 30) and COPD (n = 20) individuals with and without AAT deficiency.ResultsAfter 18 h of cell culture the basal release of MMP-9 was 2.5-fold, p < 0.02 greater, whereas IL-8 was 1.8-fold (p < 0.01) lower from COPD patient monocytes than from controls. LPS-stimulated release of IL-6 and MCP-1 was greater from COPD patients monocytes relative to controls, while activation of control cells resulted in enhanced secretion of ICAM-1 and MMP-9 compared to COPD patients. Independent of disease status, monocytes from PiZZ AAT carriers released less TNFα (by 2.3-fold, p < 0.03).ConclusionsThe basal and LPS-stimulated secretion of specific pro-inflammatory molecules from circulating monocytes differs between healthy and COPD subjects. These findings may be valuable for further studies on the mechanisms involved in recruitment and activation of inflammatory cells in COPD.

Esomeprazole 20mg Provides More Effective Intragastric Acid Control than Maintenance-Dose Rabeprazole, Lansoprazole or Pantoprazole in Healthy Volunteers

ObjectiveA high proportion of patients with gastro-oesophageal reflux disease experience recurrence of symptoms within a year of initial treatment. The key to preventing relapse is an effective maintenance therapy that maintains intragastric pH >4. This study was conducted to compare the effects on intragastric pH of maintenance doses of four proton pump inhibitors: esomeprazole 20mg, lansoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg.Study participants and methodsThree standardised, randomised, two-way crossover studies were performed in a total of 108 Helicobacter pylori-negative healthy subjects. Intragastric pH was monitored on day 5 of once-daily oral dosing. The percentage of time of a 24-hour period with intragastric pH >4 and 24-hour median pH were measured on day 5.ResultsThe mean percentage of time with intragastric pH >4 on day 5 was significantly longer following esomeprazole 20mg compared with either lansoprazole 15mg (esomeprazole 50.4% vs lansoprazole 43.0%, p = 0.026), rabeprazole 10mg (esomeprazole 59.8% vs rabeprazole 51.7%, p = 0.011) or pantoprazole 20mg (esomeprazole 59.6% vs pantoprazole 39.5%, p < 0.0001).ConclusionsMaintenance dose esomeprazole 20mg provided greater acid control and maintained intragastric pH >4 for a longer period of time than maintenance dose lansoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg in healthy subjects.

Expression of Toll-like receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis.

BackgroundAllergic rhinitis is an inflammatory disease of the upper airway mucosa that also affects leukocytes in bone marrow and peripheral blood. Toll-like receptor 9 (TLR9) is a receptor for unmethylated CpG dinucleotides found in bacterial and viral DNA. The present study was designed to examine the expression of TLR9 in the nasal mucosa and in leukocytes derived from different cellular compartments during symptomatic allergic rhinitis.MethodsThe study was based on 32 patients with seasonal allergic rhinitis and 18 healthy subjects, serving as controls. Nasal biopsies were obtained before and after allergen challenge. Bone marrow, peripheral blood and nasal lavage fluid were sampled outside and during pollen season. The expression of TLR9 in tissues and cells was analyzed using immunohistochemistry and flow cytometry, respectively.ResultsTLR9 was found in several cell types in the nasal mucosa and in different leukocyte subpopulations derived from bone marrow, peripheral blood and nasal lavage fluid. The leukocyte expression was generally higher in bone marrow than in peripheral blood, and not affected by symptomatic allergic rhinitis.ConclusionThe widespread expression of TLR9 in the nasal mucosa along with its rich representation in leukocytes in different compartments, demonstrate the possibility for cells involved in allergic airway inflammation to directly interact with bacterial and viral DNA.

Concentration-dependent effects of native and polymerised α1-antitrypsin on primary human monocytes, in vitro

SummaryBackgroundα1-antitrypsin (AAT) is one of the major serine proteinase inhibitors controlling proteinases in many biological pathways. There is increasing evidence that AAT is able to exert other than antiproteolytic effects. To further examine this question we compared how various doses of the native (inhibitory) and the polymerised (non-inhibitory) molecular form of AAT affect pro-inflammatory responses in human monocytes, in vitro. Human monocytes isolated from different donors were exposed to the native or polymerised form of AAT at concentrations of 0.01, 0.02, 0.05, 0.1, 0.5 and 1 mg/ml for 18 h, and analysed to determine the release of cytokines and to detect the activity of NF-κB.ResultsWe found that native and polymerised AAT at lower concentrations, such as 0.1 mg/ml, enhance expression of TNFα (10.9- and 4.8-fold, p < 0.001), IL-6 (22.8- and 23.4-fold, p < 0.001), IL-8 (2.4- and 5.5-fold, p < 0.001) and MCP-1 (8.3- and 7.7-fold, p < 0.001), respectively, compared to buffer exposed cells or cells treated with higher doses of AAT (0.5 and 1 mg/ml). In parallel to increased cytokine levels, low concentrations of either conformation of AAT (0.02–0.1 mg/ml) induced NF-κB p50 activation, while 1 mg/ml of either conformation of AAT suppressed the activity of NF-κB, compared to controls.ConclusionsThe observations reported here provide further support for a central role of AAT in inflammation, both as a regulator of proteinase activity, and as a signalling molecule for the expression of pro-inflammatory molecules. This latter role is dependent on the concentration of AAT, rather than on its proteinase inhibitory activity.

Gene profiling reveals decreased expression of uteroglobin and other anti‐inflammatory genes in nasal fluid cells from patients with intermittent allergic rhinitis

Background Intermittent allergic rhinitis (IAR) results from interactions between a large number of pro‐ and anti‐inflammatory mediators. Little is known about anti‐inflammatory mediators in IAR. DNA microarrays allow simultaneous analysis of the whole transcriptome in a sample.

Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor

The existence of a link between inflammation in upper and lower airways is well established. It may therefore be assumed that the nose could be used to study inflammatory events in the lower airways.

Exhaled breath condensate-site and mechanisms of formation

Exhaled breath condensate (EBC) analysis is a promising tool for diagnosis and management of pulmonary diseases. Its clinical usefulness is still limited however due to unresolved issues around e.g. reproducibility, anatomical site of origin of EBC solutes and mechanisms of EBC formation. To gain some knowledge on these issues, three different airway deposition patterns of an aqueous aerosol containing technetium-99m were studied in eight healthy non-smoking subjects. EBC was collected 20 min after each radioaerosol administration and analyzed for gamma radiation and electrolytes. Radioaerosol deposition in preferentially central lung compared with preferentially peripheral lung resulted in 3.8 times higher EBC radioactivity. EBC concentrations of Na(+) and K(+) correlated significantly indicating dilution by water vapor to be a major source of variability. Since Na(+)/K(+)- and Na(+)/S(2-)-concentration ratios, but not Na(+)/Cl(-)- or Na(+)/Ca(2+)-, were comparable to those previously reported for alveolar lining fluid (ALF), some mechanisms other than dilution are likely also to be involved. In conclusion, our findings indicate that EBC derives mainly from the central airways, that the electrolyte composition of EBC does not consistently reflect that of ALF, and that EBC concentrations of electrolytes are determined not only by ALF dilution with water vapor but also by other mechanisms.

Polymerized alpha-antitrypsin is present on lung vascular endothelium. New insights into the biological significance of alpha-antitrypsin polymerization.

Aims:  The damage to lung tissue in chronic obstructive pulmonary disease (COPD) may involve the progressive loss of pulmonary vascular endothelial cells. Endothelial binding of α1‐antitrypsin (α1‐AT) derived from plasma has been identified, and α1‐AT deficiency is a known genetic risk factor associated with α1‐AT polymerization and COPD development. Therefore, in the present study we aimed to investigate if α1‐AT is present on the lung vascular endothelium, and if it is in a polymeric form.

Lipopolysaccharide administration to the allergic nose contributes to lower airway inflammation.

Background Allergic rhinitis (AR) is an inflammatory reaction not confined to a single local compartment, but rather involving the whole airway system. Allergens known to induce AR are not always the sole trigger of the inflammatory reaction as infections and organic dust might also cause exacerbations of rhinitis and associated conditions.