Low oxygen levels decrease adaptive immune responses and ameliorate experimental asthma in mice

Abstract

Background: High-altitude therapy has been used as add-on treatment for allergic asthma with considerable success. However, the underlying mechanisms remain unclear. In order to investigate the possible therapeutic effects of high-altitude therapy on allergic asthma, we utilized a new in vivo mouse model. Methods: Mice were treated with house dust mite (HDM) extract over 4 weeks and co-exposed to 10% oxygen (Hyp) or room air for the final 2 weeks. Experimental asthma was assessed by airway hyper-responsiveness, mucus hypersecretion and inflammatory cell recruitment. Isolated immune cells from mouse and allergic patients were stimulated in vitro with HDM under Hyp and normoxia in different co-culture systems to analyse the adaptive immune response. Results: Compared to HDM-treated mice in room air, HDM-treated Hyp-mice displayed ameliorated mucosal hypersecretion and airway hyper-responsiveness. The attenuated asthma phenotype was associated with strongly reduced activation of antigen-presenting cells (APCs), effector cell infiltration and cytokine secretion. In vitro, hypoxia almost completely suppressed the HDM-induced adaptive immune response in both mouse and human immune cells. While hypoxia did not affect effector T-cell responses per-se, it interfered with antigen-presenting cell (APC) differentiation and APC/effector cell crosstalk. Conclusions: Hypoxia-induced reduction in the Th2-response to HDM ameliorates allergic asthma in vivo. Hypoxia interferes with APC/T-cell crosstalk and confers an unresponsive phenotype to APCs.

Microarray-Based Prediction of Polycythemia after Exposure to High Altitudes

“…At short timescales, the impact on the adaptive immune response cut a striking figure. The adaptive immune system relies on B cells and T cells, and in vitro experiments demonstrated that the human adaptive immune response is dependent on the oxygen level [ 23 ]. CX3CR1 is stably expressed on CD8+ T cells [ 24 ], and its expression was highly suppressed on the third day following a quick climb to a high altitude.…”

Intermittent hypoxic pretreatment exacerbates house dust mite‐induced asthma airway inflammation

“…Additionally, hypoxia exacerbates asthma through involvement in the renin‐angiotensin system, contributing to epithelial‐to‐mesenchymal transition and airway remodeling 21 . However, contrasting findings suggest that hypoxia can mitigate allergic airway inflammation and improve airway remodeling, yielding beneficial effects on asthma 22–24 . Low oxygen levels induced human umbilical extracellular vesicles from cord mesenchymal stem cells, demonstrating the potential to alleviate allergic airway inflammation and airway remodeling in a chronic asthma mouse model 22 .…”

“… 21 However, contrasting findings suggest that hypoxia can mitigate allergic airway inflammation and improve airway remodeling, yielding beneficial effects on asthma. 22 , 23 , 24 Low oxygen levels induced human umbilical extracellular vesicles from cord mesenchymal stem cells, demonstrating the potential to alleviate allergic airway inflammation and airway remodeling in a chronic asthma mouse model. 22 Hypoxia further alleviates allergic asthma by downregulating the MAPK signaling pathway.…”

Preparation of Budesonide-Loaded Liposomal Nanoparticles for Pulmonary Delivery and Their Therapeutic Effect in OVA-Induced Asthma in Mice

“…Airway mucus hypersecretion is one of the pathophysiological features of asthma. 39 Since clinicians identified mucus plugs as a fatal factor in asthmatic patients in the 1880s, his phenomenon has been continuously and rigorously studied. 24 Consequently, whether airway mucus is effectively cleared is critical for evaluating the effect of asthma treatment.…”