The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130–fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4⁺CD25⁺ Tregs with increased immunosuppressive capacities. CD4⁺CD25⁺ but not CD4⁺CD25^– lung T cells selectively expressed the IL-6R α chain and showed IL-6–dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4⁺CD25⁺ T cells isolated from anti–IL-6R antibody–treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.

The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV₁). After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV₁, whereas placebo was associated with a 1% increase in the AUC for FEV₁ (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV₁, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo. Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.)

Epidemiologic studies have shown an increased prevalence of allergic asthma in children living in a German smelter area (Hettstedt) compared with a cohort who live in a nonindustrialized area (Zerbst). However, it is not known whether ambient particles (particulate matter2.5 [PM2.5]) from these areas induce distinct lung inflammation, which might be an explanation for this difference. Therefore, 100 μg of PM2.5 suspensions, collected simultaneously in the two areas, were instilled through a bronchoscope into contralateral lung segments of 12 healthy volunteers. PM2.5 from both Hettstedt and Zerbst increased the number of leukocytes in the bronchoalveolar lavage performed 24 hours later. PM2.5 from Hettstedt, but not Zerbst, induced a significant influx of monocytes (Hettstedt: 7.0% vs. Zerbst: 4.3%) without influencing the expression of surface activation markers on monocytes and alveolar macrophages. Oxidant radical generation of bronchoalveolar lavage cells and cytokine concentration (interleukin-6 and tumor necrosis factor-α) in bronchoalveolar lavage fluid was significantly increased after instillation of Hettstedt PM2.5. We conclude that environmentally relevant concentrations of PM2.5 from the smelter area induced distinct airway inflammation in healthy subjects with a selective influx of monocytes and increased generation of oxidant radicals. The higher concentration of transition metals in PM2.5 from Hettstedt might be responsible for this increased inflammation.

Assessment of cardiac output is an important part of the management of patients with pulmonary hypertension. The accuracy of the thermodilution technique in patients with low cardiac output or severe tricuspid regurgitation has been questioned. To address this issue, we simultaneously compared 105 cardiac output measurements by the Fick method and thermodilution in 35 patients with pulmonary hypertension. Moreover, we evaluated the acetylene rebreathing technique, a noninvasive method of determining cardiac output. The mean difference ± 95% limit of agreement between thermodilution and the Fick method was + 0.01 ± 1.1 L/min. The mean difference ± 95% limit of agreement between acetylene rebreathing and the Fick method was − 0.23 ± 1.14 L/min. Neither the mean agreement nor the 95% limits of agreement of both thermodilution and acetylene rebreathing with the Fick method were affected by the presence of low cardiac output or severe tricuspid regurgitation. We conclude that thermodilution and acetylene rebreathing are useful tools for assessing cardiac output in patients with pulmonary hypertension, even in the presence of low cardiac output or severe tricuspid regurgitation.

Allergic asthma is thought to be the result of an inappropriate specific immune response against common environmental antigens. However, studies of animal asthma models have also linked the innate immune system, in particular complement factors C3a and C5, to murine airway hyperresponsiveness. Because the possible role of these anaphylatoxins in patients with asthma is not understood, we tested the hypothesis that C3a and C5a will increase in the bronchoalveolar lavage (BAL) fluid of patients with asthma after segmental allergen provocation. In a group of 15 subjects with mild asthma we found a significant upregulation of C3a and C5a 24 h after allergen challenge compared with baseline values (p < 0.01). In a control group of healthy volunteers the concentrations remained basically unchanged. Furthermore, we found a strong correlation between both anaphylatoxins and the number of eosinophils (p < 0.01) and, to a lesser degree, with the number of neutrophils (p < 0.05) in BAL fluid. These data suggest a contribution of anaphylatoxins C3a and C5a to the pathogenesis in asthma. However, the pathogenic role of these substances in relation to asthma remains to be elucidated, for example, by using anaphylatoxin receptor blockers as a possible new therapeutic principle.