adrenomedullin and Hyperoxia

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is an infantile lung disease characterized by aberrant angiogenesis and impaired resolution of lung injury. Adrenomedullin (AM) signals through calcitonin receptor-like receptor and receptor activity-modifying protein 2 and modulates lung injury initiation. However, its role in lung injury resolution and the mechanisms by which it regulates angiogenesis remain unclear. Consequently, we hypothesized that AM resolves hyperoxia-induced BPD and PH via endothelial nitric oxide synthase (NOS3). AM-sufficient (ADM

Topics: Adrenomedullin; Animals; Bronchopulmonary Dysplasia; Endothelial Cells; Female; Humans; Hyperoxia; Hypertension, Pulmonary; Lung; Lung Injury; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Receptor Activity-Modifying Protein 2; Signal Transduction

Topics: Adrenomedullin; Animals; Animals, Newborn; Humans; Hyperoxia; Infant, Newborn; Infant, Premature; Lung; Mice; Receptors, Adrenomedullin; Signal Transduction

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants that is characterized by alveolar simplification and decreased lung angiogenesis. Hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD in premature infants. Adrenomedullin (AM) is an endogenous peptide with potent angiogenic, anti-oxidant, and anti-inflammatory properties. Whether AM regulates hyperoxic injury in fetal primary human lung cells is unknown. Therefore, we tested the hypothesis that AM-deficient fetal primary human pulmonary microvascular endothelial cells (HPMEC) will have increased oxidative stress, inflammation, and cytotoxicity compared to AM-sufficient HPMEC upon exposure to hyperoxia. Adrenomedullin gene (Adm) was knocked down in HPMEC by siRNA-mediated transfection and the resultant AM-sufficient and -deficient cells were evaluated for hyperoxia-induced oxidative stress, inflammation, cytotoxicity, and Akt activation. AM-deficient HPMEC had significantly increased hyperoxia-induced reactive oxygen species (ROS) generation and cytotoxicity compared to AM-sufficient HPMEC. Additionally, AM-deficient cell culture supernatants had increased macrophage inflammatory protein 1α and 1β, indicating a heightened inflammatory state. Interestingly, AM deficiency was associated with an abrogated Akt activation upon exposure to hyperoxia. These findings support the hypothesis that AM deficiency potentiates hyperoxic injury in primary human fetal HPMEC via mechanisms entailing Akt activation.

Topics: Adrenomedullin; Bronchopulmonary Dysplasia; Cell Death; Cells, Cultured; Endothelial Cells; Fetus; Gene Knockdown Techniques; Humans; Hyperoxia; Infant, Newborn; Lung; Lung Injury; Oxidative Stress; Proto-Oncogene Proteins c-akt

Oxidative stress and inflammation are involved in the pathogenesis of acute lung injury (ALI). Adrenomedullin (AM) is an endogenous peptide with anti-inflammatory and antioxidant properties. This study investigated that whether AM treatment may ameliorate hyperoxia-induced ALI in rats via inhibition of oxidative stress and inflammation. Rats were randomized to receive continuous intravenous infusion of AM or saline through a microosmotic pump, and then ALI was induced by exposing the animals in sealed cages >95% oxygen for 72 h. Exposure to hyperoxia caused lung injury as increased infiltration of inflammatory cells and disruption of lung architecture. AM administration markedly improved these changes. Additionally, AM administration significantly increased glutathione peroxidase and superoxide dismutase activities. Meanwhile, hyperoxia-induced increase of lipid hydroperoxide level was markedly reduced by AM treatment. Moreover, nuclear factor-kappa B-DNA-binding activity, and production of the inflammatory mediators interleukin-6, keratinocyte-derived chemokine, and matrix metalloproteinase 9, were significantly inhibited by AM treatment. AM ameliorates hyperoxia-induced ALI in rats by suppression of oxidative stress and inflammation.

Topics: Acute Lung Injury; Adrenomedullin; Animals; Chemokines; Glutathione Peroxidase; Hyperoxia; Inflammation; Interleukin-6; Lipid Peroxides; Lung; Male; Matrix Metalloproteinase 9; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase