Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung injury (ALI) characterized by a sudden onset and a profound inability of the lungs to oxygenate the blood (hypoxemia). There are no known therapies for ARDS except using low volumes on mechanical ventilation (MV), which still has an unacceptably high mortality rate of 30%. The combination of sepsis plus MV (`two-hit) significantly increases the risk for developing ARDS. Interleukin-1? (IL-1?) and IL-1? are implicated in the pathogenesis of ARDS. While both IL-1? and IL-1? are produced in a pro form, cleavage of IL-1? is required for its secretion and activation, while both the cleaved and pro-form of IL-1? are active. Our preliminary data indicate that pro- IL-1? is released from necrotic M? after LPS inhalation, which leads to vascular leakage and PMN recruitment into the lungs. However, for maturation and release of IL-1?, activation of the inflammasome is required. We showed that NLRP3 inflammasome is activated in M? by mitochondrial (Mt) dysfunction followed by oxidized MtDNA binding to NLRP3. Mt damage simultaneously leads to activation of repair systems such as autophagy and mitophagy that oppose cell death. Recent reports suggest that both mitophagy and Mt biogenesis may serve a protective role in sepsis and mitigate ALI. We developed a mouse model in which MV triggers M? Mt dysfunction and cell death, and intratracheal LPS followed by MV lead to sequential release of IL-1? and IL-1? secretion and the development of ALI, with PMN infiltration, alveolar edema, chemokine secretion, and hypoxemia. When IL-1? signaling was disrupted by the absence of caspase-1 or NLRP3, or by IL-1R antagonist, mice demonstrated equal levels of inflammation compared to controls, but failed to develop hypoxemia, indicating that the mechanism of hypoxemia in ALI is dependent on IL-1 signaling. Both endothelial cells (EC) and smooth muscle cells (SMC) have been implicated in the mechanism of ALI-induced hypoxemia and are targets of IL-1 signaling. These observations lead us to hypothesize that the development of ALI and hypoxemia in LPS+MV requires sequential release of IL-1? from LPS-induced necrotic M?, followed by IL-1? secretion by NLRP3 inflammasome activation in AM during MV. Mitophagy and mitochondrial biogenesis oppose LPS+MV induced acute lung injury and hypoxemia by inhibiting inflammasome activation and preserving tissue function. To test these hypotheses we propose the following specific aims: 1) Determine the role of IL-1? in the development of hypoxemia in LPS+MV acute lung injury. 2) Determine the role of IL-1 signaling in LPS+MV-induced hypoxemia. 3) Determine the role of mitophagy and mitochondria biogenesis in LPS+MV acute lung injury. These studies will help determine novel mechanisms underlying IL-1? and?? dependent hypoxemia in ALI and ARDS, and will identify a new area of potential therapeutics for sepsis patients with ARDS on MV, a condition that still carries over 30% mortality rate for which no treatments currently exist.
The application seeks to address the novel role of sequential release of IL-1alpha and IL-1beta, macrophage death and mitochondrial damage in the lungs during sepsis and mechanical ventilation, and investigates novel treatments that generate new mitochondria and remove damage mitochondria (which drives inflammation).
|Noval Rivas, Magali; Lee, Youngho; Wakita, Daiko et al. (2017) CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract-Induced Murine Model of Kawasaki Disease. Arthritis Rheumatol 69:410-421|
|Domiciano, Talita P; Wakita, Daiko; Jones, Heather D et al. (2017) Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis. Sci Rep 7:41539|
|Wakita, Daiko; Kurashima, Yosuke; Crother, Timothy R et al. (2016) Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm. Arterioscler Thromb Vasc Biol 36:886-97|
|Tumurkhuu, Gantsetseg; Shimada, Kenichi; Dagvadorj, Jargalsaikhan et al. (2016) Ogg1-Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis. Circ Res 119:e76-90|