Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0476273 (respiratory distress)
 19,632 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute lung injury (ALI) associated with sepsis and acute respiratory distress syndrome (ARDS) is a leading cause of death of critically ill patients in U.S. Our understanding of the pathobiology and mechanisms underlying ALI is increasing as a result of basic research and advances in molecular biology. Unfortunately, morbidity and mortality from ALI and ARDS still remains unacceptably high (30-40%). The major reason underlying lag in improvement in outcome is the lack of novel and specific therapies for ALI and ARDS. To begin to address this issue, we developed novel long-acting biocompatible and biodegradable phospholipid micelles (size, approximately 15 nm) to inhibit triggering receptor expressed on myeloid cells 1 (TREM-1), reactive oxygen species and Hsp90, key effectors thought to underlie ALI, in vivo. Realizing short half-life of peptide drugs (minutes) hampers their clinical use, we invented micellar TREM-1 peptide and glucagon-like peptide-1(7-36) amide (GLP-1) where each peptide drug is stabilized in its active form (alpha-helix) and its bioactivity is prolonged for hours in vivo. Likewise, water-insolubility of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a selective Hps90 inhibitor, constrains its use in humans. Accordingly, self-association of 17-AAG with these micelles overcomes this limitation while at the same time increasing its stability and bioavailability. These long-acting micellar nanomedicines provide significant advancement in the treatment of experimental of ALI which could then be extended to critically ill patients.
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PMID:Long-acting, multi-targeted nanomedicine: addressing unmet medical need in acute lung injury. 2020 Dec 23

Hyperoxia-induced injury to the developing lung, impaired alveolarization, and dysregulated vascularization are critical factors in the pathogenesis of bronchopulmonary dysplasia (BPD); however, mechanisms for hyperoxia-induced development of BPD are not fully known. In this study, we show that TREM-1 (triggering receptor expressed on myeloid cells 1) is upregulated in hyperoxia-exposed neonatal murine lungs as well as in tracheal aspirates and lungs of human neonates with respiratory distress syndrome and BPD as an adaptive response to survival in hyperoxia. Inhibition of TREM-1 function using an siRNA approach or deletion of the Trem1 gene in mice showed enhanced lung inflammation, alveolar damage, and mortality of hyperoxia-exposed neonatal mice. The treatment of hyperoxia-exposed neonatal mice with agonistic TREM-1 antibody decreased lung inflammation, improved alveolarization, and was associated with diminished necroptosis-regulating protein RIPK3 (receptor-interacting protein kinase 3). Mechanistically, we show that TREM-1 activation alleviates lung inflammation and improves alveolarization through downregulating RIPK3-mediated necroptosis and NLRP3 (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3) inflammasome activation in hyperoxia-exposed neonatal mice. These data show that activating TREM-1, enhancing angiopoietin 1 signaling, or blocking the RIPK3-mediated necroptosis pathway may be used in new therapeutic interventions to control adverse effects of hyperoxia in the development of BPD.
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PMID:TREM-1 Attenuates RIPK3-mediated Necroptosis in Hyperoxia-induced Lung Injury in Neonatal Mice. 3028 32