Investigation of the Role of Il-33/St2 in Exacerbating Acute Respiratory Distress Syndrome-Induced Nf-Κb/Mapk Signaling Pathways through Ros Accumulation Using an Il33-/- Mouse Model

Background: Despite the current state-of-the-art treatment modality, both acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) still contribute to the high mortality of patients hospitalized for pulmonary diseases. Ineffective treatments for ARDS could be due to their various causes such as sepsis, inhalation of harmful substances, severe pneumonia, and trauma. Inflammatory response in ALI/ARDS is initiated and modulated by a complex network of cytokines and other proinflammatory molecules. Interleukin (IL)-33, a novel profibrogenic cytokine, signals through its receptor, ST2, to promote the initiation and progression of pulmonary fibrosis by mobilizing inflammatory cells and augmenting profibrogenic cytokine (ie, IL-13 and TGF-β) production in ST2 and macrophage-dependent manner. Rationale: IL-33 is constitutively expressed in lung epithelial cells. Our preliminary data showed that ARDS triggers lung injury through the upregulation of the expressions of IL-33 and ST2 in lung parenchyma, which in turn may lead to recruitment of MyD88/ TRAF6/ IRAK-1/4 complex. In addition, IL-33/ST2 axis activates its downstream signaling molecules [ie, NF-κB or mitogen-activated protein kinase (p38, ERK and ERK)], all of which are strong inducers of pro-inflammatory cytokine and chemokine secretion together with NADPH oxidases. Moreover, NADPH oxidases may exacerbate the generation of reactive oxygen species (ROS) through IL-33/ST2 signaling pathway. We aim at testing the hypothesis that IL-33 effectively exacerbates ARDS-induced lung injury for which the underlying mechanism is believed to be the accumulation of ROS from activation of the NF-κB/MAPK signaling cascades as a result of interaction between epithelial-derived IL-33 and ST2. Accordingly, the aims of the proposed 3-year study are: (1) To induce an obese IL33-/- mice fed with high fat diet and establish an ARDS-associated lung injury mice model by exposing to 100% oxygen for 72 hours; (2) To examine epithelial-derived IL-33 and its receptor ST2 are altered after ARDS-induced lung injury in obese diabetic and wild-type mice; (3) To determine IL-33/ST2 axis is involved in ROS-induced alveolar cell death after ADRS induction and (4) further to investigate underlying mechanisms of IL-33/ST2 axis responsible for cell death in IL33-/- mice, obese IL33-/- mice and wild-type mice; (5) To verify the suppressive effects of anti-IL-33 antibody and adenovirus-mediated soluble ST2 protein on ARDS-induced lung parenchymal injury (fibrosis) and airway inflammatory responses in obese diabetic and wild-type mice. Significance: The results of the proposed study not only will enhance our understanding of the association between diabetes and ARDS development, but will also help in identifying a potential therapeutic target through exploring the role of IL-33. Of particular importance is that our results will provide us with essential preclinical information about the use of anti-IL-33 antibody or recombinant soluble ST2 as therapeutic tool for ARDS patients refractory to the current conventional therapy.

Project ID:PC10507-0284
External Project ID:MOST105-2314-B182-044