Romain Pauwels

Airway IgG counteracts specific and bystander allergen-triggered pulmonary inflammation by a mechanism dependent on Fc gamma R and IFN-gamma.

Besides IgE, the Ab isotype that gives rise to sensitization and allergic asthma, the immune response to common inhalant allergens also includes IgG. Increased serum titers of allergen-specific IgG, induced spontaneously or by allergen vaccination, have been implicated in protection against asthma. To verify the interference of topical IgG with the allergen-triggered eosinophilic airway inflammation that underlies asthma, sensitized mice were treated by intranasal instillation of specific IgG, followed by allergen challenge. This treatment strongly reduced eosinophilic inflammation and goblet cell metaplasia, and increased Th1 reactivity and IFN-γ levels in bronchoalveolar lavage fluid. In contrast, inflammatory responses were unaffected in IFN-γ-deficient mice or when applying F(ab′)2. Although dependent on specific allergen-IgG interaction, inflammation triggered by bystander allergens was similarly repressed. Perseverance of inflammation repression, apparent after secondary allergen challenge, and increased allergen capture by alveolar macrophages further characterized the consequences of topical IgG application. These results assign a novel protective function to anti-allergen IgG namely at the local level interference with the inflammatory cascade, resulting in repression of allergic inflammation through an FcγR- and IFN-γ-dependent mechanism. Furthermore, these results provide a basis for topical immunotherapy of asthma by direct delivery of anti-allergen IgG to the airways.

Modulation by 5-HT1A receptors of the 5-HT2 receptor-mediated tachykinin-induced contraction of the rat trachea in vitro.

In the Fisher 344 rat, tachykinins have been shown to cause the release of 5‐hydroxytryptamine (5‐HT) from airway mast cells, which then causes direct smooth muscle activation as well as the release of acetylcholine from cholinergic nerves. The aim of the present study was to examine the modulatory effects of 5‐HT receptors on the neurokinin A (NKA)‐induced release of endogenous 5‐HT and airway smooth muscle contraction in the isolated Fisher 344 rat trachea. The selective 5‐HT2 receptor antagonist ketanserin (0.1u2003μM) produced an almost complete inhibition of the contractions caused by NKA (n=4, P<0.0001, two‐way ANOVA), and a significant rightward shift of the concentration‐response curve to 5‐HT (n=8, P<0.001, two‐way ANOVA). The partial agonist for 5‐HT1A receptors, 8‐OH‐DPAT (1u2003μM), and the full agonist for 5‐HT1 receptors, 5‐CT (0.3u2003μM), potentiated the submaximal contractions induced by the 5‐HT2 receptor agonist α‐methyl‐5‐HT (0.1u2003μM) (n=4; P<0.005 and P<0.05, respectively). 8‐OH‐DPAT (1u2003μM), as well as the 5‐HT1A receptor antagonists pMPPI, SDZ 216525 and NAN‐190 (0.1u2003μM each), caused significant inhibition of the tracheal contractions induced both by NKA (10u2003u2003nM–3u2003u2003μM) and 5‐HT (10u2003nM–10u2003μM) (n=4–10). This suggests that activation of 5‐HT1A receptors potentiates the 5‐HT2 receptor‐mediated contractions. SDZ 216525 (0.1u2003μM) significantly reduced the maximal contraction produced by 1u2003μM NKA (n=10, P<0.001), without affecting the release of endogenous 5‐HT. These data rule out the involvement of a 5‐HT1A receptor‐mediated positive feedback mechanism of the 5‐HT release from mast cells. Even in the presence of atropine (1u2003μM), 8‐OH‐DPAT (1u2003μM) further reduced the maximal NKA‐induced contraction (n=4, P<0.0001), while the contractions of the rat isolated trachea induced by electrical field stimulation and the concentration‐response curve to carbachol were unaffected by pMPPI (0.1u2003μM), SDZ 216525 (0.1u2003μM), NAN‐190 (0.1u2003μM) and 8‐OH‐DPAT (1u2003μM) (n=4–6). These data demonstrate that the 5‐HT1A receptor‐mediated potentiation of contractile responses is not due to non‐specific inhibition of airway smooth muscle contraction or to modulation of postganglionic nerve activation. The selective 5‐HT1B/1D receptor antagonist GR 127935, the selective 5‐HT3 receptor antagonist tropisetron and the selective 5‐HT4 receptor antagonists SB 204070 and GR 113808 (0.1u2003μM each) had no effect on the concentration‐response curve for NKA (n=6–10), ruling out the involvement of 5‐HT1B/1D, 5‐HT3 and 5‐HT4 receptors. The α‐adrenoreceptor antagonist phentolamine (1u2003μM) had no effect on the 5‐HT‐induced contractions (n=4), ruling out the involvement of α‐adrenoreceptors. In conclusion, the tachykinin‐induced contraction of the F334 rat isolated trachea is mediated by the stimulation of 5‐HT2 receptors. Activation of 5‐HT1A receptors located on airway smooth muscle potentiates the direct contractile effects of 5‐HT2 receptor activation. The 5‐HT1B/1D, 5‐HT3 and 5‐HT4 receptors are not involved in the NKA‐induced contraction of rat airways.

Genetic control of indirect airway responsiveness in the rat

Many of the airway responses to endogenous and exogenous stimuli are caused by indirect mechanisms such as the activation of neurons and/or inflammatory cells. In the present study we compare the bronchoamstrictor and the plasma protein extravasation response to adenosine and tachykinins in two highly inbred rat strains. F344 and BDE. BDE‐rats have a bronchoconstrictor response to adenosine at lower doses. Challenge with the A3‐adenosine receptor agonist APNEA demonstrates that the difference in airway responsiveness to adenosine between BDE‐ and F344‐rats is probably related to a higher number of A3‐receptors on the airway mast cells of BDE‐rats. In contrast. F344‐rats have a higher airway responsiveness to lachykinins than BDE‐rats. Taehykinins cause bronchoconstriction in F344‐rats mainly by an indirect mechanism, involving stimulation of NK1‐receptors and mast cell activation. In BDE‐rats they cause bronchoconstriction by a direct effeet on airway smooth muscle via activation of NK2‐receptors. Finally we also observed a difference between F344‐and BDE‐rats with regard to the mechanisms involved in the plasma protein extravasation in the airways caused by substance P or capsuicin. In K344‐rats but not in BDE‐rats mast cell activation and the release of 5‐hydroxytryptamine is partly responsible for this plasma protein extravasation.

Modulatory Effects of Freund’s Adjuvant Treatment on Mast Cell Histamíne Release and Homocytotropic Antibody Synthesis

The present study examines the influence of Freunds complete adjuvant (FCA) injections on sensitized PVG rats with respect to serum levels of IgE and IgG2 alpha antibodies and total IgE (all assessed by radioimmunoassays) and the capacity of serosal mast cells to release histamine on challenge in vitro with immunological secretagogues (specific antigen, anti-IgE, concanavalin A) or with compound 48/80. The rats were immunized with 10 micrograms ovalbumin (OA); alum, Bordetella pertussis vaccine, or silica gel were employed as adjuvants. Treatment with FCA was performed by single intraperitoneal injections 3, 2, or 1 week(s) before or 1 or 2 weeks after sensitization. Tests were conducted 3 weeks after sensitization. The results show that the effect of FCA treatment varied reproducibly with the adjuvant employed for sensitization and with the timing of the FCA administration. FCA treatment could either increase, fail to affect, or decrease total serum IgE and OA-IgG2 alpha antibody levels as well as serosal mast cell responsiveness, whereas OA-IgE antibody responses were decreased or not affected. Moreover, serum levels of OA-IgE and OA-IgG2 alpha antibodies and total IgE were affected by FCA treatment independently of each other. Finally, serosal mast cell responsiveness to a given secretagogue could be influenced by the FCA treatment apparently independently of that to other secretagogues. A salient finding was that effects of FCA treatment on mast cell responsiveness did not necessarily conform to effects on antibody synthesis. Collectively, these data support the opinion that the mechanisms of action of the IgE-promoting adjuvants employed differ and suggest that the expression of serosal mast cell responsiveness to each examined secretagogue can be regulated separately. They also suggest that the serosal mast cell sensitizing capacity of homocytotropic antibodies may not be adequately quantified by immunochemical methods employing reagents prepared against IgE and IgG2 alpha protein.

Genetic factors controlling airway responsiveness

SummaryThe airways have a repertoire of defense mechanisms against stimuli entering the tracheobronchial tree. Bronchial asthma can be regarded as an exaggerated airway response to different exogenous stimuli. There is indirect evidence that asthmatics form a heterogeneous population characterized by an increased responsiveness in one or more of these airway defense mechanisms. Furthermore, human investigations and animal experiments suggest that both environmental and genetic factors operate at these different levels. The aim of the present paper is to review the evidence that genetic factors control the airway response to exogenous stimuli and correlate these observations with the evidence that genetic factors are involved in the pathogenesis of human bronchial asthma.The airways are controlled by a complex network of defense mechanisms that aim at guarding the normal physiological function of the airways, i.e., the conduction and conditioning of air (1,2). The airway defense mechanisms can be divided roughly in the following more or less interwoven aspects1.Reflex bronchoconstriction either by local axon reflexes, or vagal reflexes via the central nervous system;2.Increase in mucus production and mucociliary clearance;3.Cough;4.Inflammation involving different cell types, such as the airway epithelial cells, macrophages, mast cells, and the influx of secondary cells such as neutrophils, eosinophils, and platelets; and5.Immunological response resulting in a more rapid and a more intense inflammatory and possibly also reflex response.

Review of effectiveness of cefodizime in the treatment of lower respiratory tract infections with parenchymal involvement

SummaryThe efficacy of cefodizime (CDZ) in lower respiratory tract infections (LRTI) with parenchymal involvement was assessed by the analysis of data from 919 patients who participated in four controlled, randomized studies and three open studies. Sputum bacteriology and a chest x-ray were performed at baseline and after therapy. A total of 778 patients were evaluable for clinical efficacy and 451 for bacteriological efficacy. The most frequent pathogen wasStreptococcus pneumoniae, followed byStaphylococcus aureus, Klebsiella pneumoniae andHaemophilus influenzae. CDZ 1 g b.i.d., 2 g b.i.d. and 2 g once daily achieved clinical and bacteriological cure rates above 90%, which matched those observed with the comparators (cefuroxime 1.5 g t.i.d. and cefotaxime 2 g b.i.d.). No significant differences in clinical and bacteriological outcome were detected when the various CDZ dosage regimens were compared. 1 g CDZ b.i.d. is therefore recommended as the regimen of choice for the treatment of LRTI with parenchymal involvement, with CDZ 2 g once daily as an alternative.ZusammenfassungDie Wirksamkeit von Cefodizim (CDZ) bei der Behandlung von Infektionen der tiefen Atemwege mit Parenchymbeteiligung wurde anhand von vier kontrollierten, randomisierten und drei offenen klinischen Studien mit insgesamt 919 Patienten beurteilt. Zu Studienbeginn und -ende wurden Thoraxröntgen und Sputumbakteriologie durchgeführt. 778 Patienten waren hinsichtlich der klinischen Wirksamkeit, 451 bezüglich der bakteriologischen Wirksamkeit auswertbar. Die häufigsten Keime warenStreptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae undHaemophilus influenzae. Sowohl mit CDZ 2 × 1 g/d als auch mit 2 × 2 g/d und 1 × 2 g/d wurden klinische und bakteriologische Heilungsraten von über 90% erzielt, ähnlich wie mit den Referenzsubstanzen, Cefuroxim 3 × 1,5 g/d und Cefotaxim 2 × 2 g/d. Zwischen den drei Dosierungsschemata von CDZ wurde kein statistisch signifikanter Unterschied festgestellt, daher wird gegenwärtig die Dosis von CDZ 2 × 1 g/d zur Behandlung von Infektionen der tiefen Atemwege mit Parenchymbeteiligung empfohlen. Ein alternatives Behandlungsschema wäre die einmal tägliche Verabreichung von 2 g CDZ.

Effect on Rat IgA Synthesis by Isotypic Suppression with an Anti-Rat Delta Heavy Chain Serum

It is highly probable that IgA precursor cells have IgD receptors during their ontogeny, however isotypic suppression with anti-delta serum did not demonstrate this possibility at least in our experimental conditions. Moreover, isotypic suppression with anti-delta serum seems ineffective in diminishing the serum levels of Ig classes other than IgD under these conditions, as IgM, IgE and IgG serum levels were relatively unaffected, at least during the first month of the rat life.