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• Articles of note…
  • Effects of inhaled salmeterol on bronchial inflammation
  • High constitutive glucocorticoid receptor β in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids
  • Effect of the early or delayed insertion of tympanostomy tubes for persistent otitis media with effusion on developmental outcomes at age 3 years
  • The role of adjuvant adenoidectomy and tonsillectomy in the outcome of the insertion of tympanostomy tubes
  • Another breakthrough in innate immunity
• Other articles of interest
• Copyright

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Articles of note… 

Effects of inhaled salmeterol on bronchial inflammation 

It is generally accepted that bronchial inflammation plays a major role in the pathogenesis of asthma and is an appropriate target of therapeutic approaches. However, it is still debated whether the long-acting β-agonists used commonly in asthma treatment have significant anti-inflammatory or even proinflammatory effects. This investigation was a double-blinded, placebo-controlled crossover study of the effect of prior inhalation treatment with the long-acting β₂-agonist salmeterol on airway responses at 5 minutes and 48 hours after segmental allergen challenge in 13 allergic asthmatics sensitive to the challenge allergen. It was found that pretreatment with salmeterol reduced the decrease in FEV₁ occurring after allergen challenge. However, there was no impressive effect of salmeterol on the inflammatory cell response to the allergen challenge. One measure of superoxide production was reduced, and the level of IL-4 was reduced in baseline bronchoalveolar lavage samples, but other indices of airway inflammation were unchanged by salmeterol therapy—neither decreased nor increased. The authors concluded that inhalation of this long-acting β₂-agonist does not significantly affect airway inflammatory responses in allergic asthma, at least during short-term therapy.

(Calhoun et al. Am J Respir Crit Care Med 2001; 163:881-6) MEDLINE

High constitutive glucocorticoid receptor β in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids 

The activities of neutrophils (PMNs) are markedly less sensitive to glucocorticoids than are T-cell activities, making it difficult to control inflammation by glucocorticoids in PMN-mediated diseases. This difference in responsiveness to glucocorticoids could be related to differences in the relative expression on these cell types of (1) the functional glucocorticoid receptor GRα and (2) the nonfunctional glucocorticoid receptor GRβ, which actually inhibits GRα activity. In this study, the expression of GRα and the expression of GRβ on PMNs and peripheral blood mononuclear cells (PBMCs) were compared through use of immunofluorescence analysis. It was found that the expression of GRα was 475+/–62 on PBMCs and 985+/–107 on PMNs. GRβ expression was 350+/–60 and 1389+/–143 on PBMCs and PMNs, respectively. Thus there was a greater ratio of the constitutive expression of GRβ to that of GRα on PMNs than on PBMCs. Expression of GRβ, but not of GRα, on PMNs increased significantly after incubation of the PMNs with the cytokine IL-8. The greater ratio of GRβ to GRα constitutive expression on PMNs than on PBMCs detected by immunofluorescence was confirmed by quantitative Western Blot analysis. There was also increased expression in the PMNs of the mRNA for GRβ at baseline and after IL-8 incubation, as determined by RNA dot blot analysis. GRβ transfection of the PMNs of mice, which normally do not express GRβ, resulted in significantly less glucocorticoid-induced death of these cells. The authors concluded that these findings can explain the decreased responsiveness of PMNs to the anti-inflammatory effects of glucocorticoid treatment, particularly in sites where PMNs are activated by cytokines such as IL-8. These findings could also indicate a mechanism by which PMNs escape glucocorticoid-induced cell death.

(Strickland et al. J Exp Med 2001;193:585-94) MEDLINE

Editor’s note: The following 2 reviews describe articles that appeared in the same issue of the New England Journal of Medicine and dealt with the tympanostomy approach to the treatment of chronic middle ear effusion, a subject of interest to allergists-immunologists. Interested individuals might also wish to read the accompanying editorial by Perrin (N Engl J Med 2001;344:1241-2).

Effect of the early or delayed insertion of tympanostomy tubes for persistent otitis media with effusion on developmental outcomes at age 3 years 

Concerns have been raised that persistent middle ear effusion in infants and young children might lead to lasting impairments of speech, language, and cognitive and psychosocial development. However, it is still unclear whether the common practice of inserting tympanostomy tubes (Tymps) in the ears of such children prevents developmental impairment. In this study by Paradise et al, 429 children with persistent middle ear effusion were randomly assigned to have Tymps inserted either as soon as feasible or up to 9 months later if effusion persisted. It was found (as the authors expected) that the children were relatively free of middle ear effusion after the Tymps were inserted. In 402 of these children, speech, language, cognition, and psychosocial development were assessed at the age of 3 years. At that time, there were no significant differences between the early-treatment group and the late-treatment group in the mean scores in a number of speech and cognitive assessments, in parent-child stress, and in behavior. The authors thought that the lack of different outcomes in their 2 treatment groups reflected neither socioeconomic factors nor a possible longer duration of previous middle ear effusion than diagnosed in their early treatment group at the initiation of the study. However, they cautioned that their findings might not apply to those children who already had sizable hearing loss and/or developmental abnormalities at the time when the Tymps were inserted. Furthermore, it is conceivable that more impressive differences in outcomes might become apparent with a longer follow-up of the 2 treatment groups.

(Paradise et al. N Engl J Med 2001;344:1179-87) MEDLINE

The role of adjuvant adenoidectomy and tonsillectomy in the outcome of the insertion of tympanostomy tubes 

There has been a debate about the usefulness of concomitant adenoidectomy or adenotonsillectomy performed at the time of tympanostomy tube (Tymp) treatment for otitis media with effusion (OME). In this study, Coyle et al reviewed hospital discharge records of 37,316 children who had received Tymps as the first surgical treatment for OME. In comparison with those having Tymp insertion alone, those who also had concomitant adenoidectomy had a significantly reduced risk for future reinsertion of Tymps (RR = 0.5) and a reduced risk of hospital readmission for conditions related to OME (RR = 0.5). These risks were even lower in the children who had adenotonsillectomy at the time of Tymp insertion. This added benefit of concomitant adenoidectomy was seen in children as young as 1 year of age but was greatest in children who were at least 3 years of age.

(Coyle et al. N Engl J Med 2001;344:1188-95) MEDLINE In the editorial accompanying these 2 reports, Perrin pointed out (1) the ongoing debate about the clinical importance of the developmental abnormalities attributed by some to persistent middle ear effusion, (2) the well-documented associated decrease in hearing acuity at the time when middle ear effusions were present, (3) the importance of a longer follow-up than to age 3 years (used by Paradise et al) in assessing developmental outcomes, and (4) the potential for inaccuracy and misinterpretation in the reliance on hospital discharge records for the information reported by Coyle et al.

Another breakthrough in innate immunity 

Toll-like receptors (TLRs) recognize pathogenassociated molecular patterns and are critical for the early innate immune response to infectious agents. Although there are 10 TLRs in humans, the ligands for only a subset have been identified. For example, TLR2 is the receptor for the bacterial cell wall component peptidylglycan, TLR4 is the receptor for responses to lipopolysaccharide, and TLR9 is the receptor for CpG DNA. In the current article, the mammalian receptor for flagellin, a principal component in bacteria that triggers innate immune system responses, has been identified. Through use of TLR-transfected cell lines, the flagellin present in the protein derived from Listeria monocytogenes is shown to activate TLR5 responses. Consistent with this, expression of flagellin in nonflagellated bacteria conferred on the bacterium the ability to activate TLR5. In addition, deletion of the flagellin gene from the bacterium abrogated TLR5-stimulating activity. Finally, responsiveness to bacterial flagellin in vivo was shown to induce signaling through the TLR pathway, inasmuch as mice deficient in the critical Toll adapter protein MyD88 did not respond to flagellin. Taken together, these findings clearly identify TLR5 as a critical receptor for bacterial flagellin, indicating that the evolutionary conserved TLR family has evolved to permit mammals to specifically detect flagellated bacterial pathogens.

(Hayashi F et al. Nature 2001;410:1099-103) MEDLINE

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Other articles of interest 

• Gilliland et al. Effects of smoking exposure on childhood asthma. Am J Respir Crit Care Med 2001;163:429-36. The effects of maternal smoking during pregnancy and environmental tobacco smoke (ETS) exposure on physician-diagnosed asthma and wheezing were assessed in 5762 school-aged children. There was an increased prevalence of physician-diagnosed asthma in children born of mothers who smoked during pregnancy but without subsequent ETS exposure during childhood. This included persistent wheezing, nocturnal wheezing, and wheezing requiring ER treatment during the previous year. In contrast, in the children whose mothers did not smoke during pregnancy but who then had ETS exposure during childhood, there was a less increased prevalence of wheezing and no increase in the frequency of physician-diagnosed asthma. However, it was unclear whether mothers who had smoked during pregnancy had really discontinued smoking in the postnatal period so that there was no ETS exposure then. MEDLINE