Abstract
The hexapeptide WKYMVm, which is a strong formyl peptide receptor (FPR) 2 agonist, exhibits pro-angiogenic, anti-inflammatory and anti-apoptotic properties. However, its therapeutic efficacy in bronchopulmonary dysplasia (BPD) has not been tested to date. Here, we investigated whether WKYMVm attenuates hyperoxia-induced lung inflammation and ensuing injuries by upregulating FPR2. The proliferation and tube formation ability of human umbilical vein endothelial cells (HUVECs), along with the level of extracellular signal regulated kinase (ERK) phosphorylation, were evaluated in vitro. Newborn mice were randomly exposed to 80% oxygen or room air for 14 days starting at birth. WKYMVm (2.5 mg/kg) was intraperitoneally administrated daily from postnatal day (P) 5 to P8. At P14, mice were sacrificed for histopathological and morphometric analyses. Along with upregulation of FPR2 and p-ERK, WKYMVm promoted HUVEC cell proliferation and tube formation in vitro. Additionally, WKYMVm promoted proliferation of human pulmonary microvascular endothelial cells (HULEC-5a) and murine pulmonary endothelial and epithelial cells in vitro. WKYMVm significantly attenuated hyperoxia-induced lung inflammation, as evidenced by increased inflammatory cytokines, neutrophils, and alveolar macrophages, and resultant lung injuries, which included impaired alveolarization and angiogenesis, an increased number of apoptotic cells, and reduced levels of growth factors in vivo, such as vascular endothelial growth factor and hepatocyte growth factor. WKYMVm attenuates hyperoxia-induced lung injuries and lung inflammation by upregulating FPR2 and p-ERK.
Highlights
Despite recent advances in neonatal intensive care medicine, bronchopulmonary dysplasia (BPD), a chronic lung disease that occurs in premature infants receiving prolonged mechanical ventilation and oxygen supplementation, still remains a major cause of mortality and morbidity in survivors with few effective treatments[1,2]
We used human umbilical vein endothelial cells (HUVECs), which are a gestational tissue-derived cell line obtained from an infant, to investigate the proangiogenic effect of WKYMVm in an in vitro assay
Recent studies demonstrated that the WKYMVm hexapeptide, which is a strong FPR2 agonist, may be a promising peptide drug due to its pro-angiogenic and anti-inflammatory properties[16,17]
Summary
Despite recent advances in neonatal intensive care medicine, bronchopulmonary dysplasia (BPD), a chronic lung disease that occurs in premature infants receiving prolonged mechanical ventilation and oxygen supplementation, still remains a major cause of mortality and morbidity in survivors with few effective treatments[1,2]. Recent studies have shown that the WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met) hexapeptide, a strong formyl receptor (FPR) 2 agonist, has pleiotropic anti-inflammatory, pro-angiogenic, anti-apoptotic and immunomodulatory effects[5] in various animal models of sepsis[6], ulcerative colitis[7], myocardial infarction[8], ischemic hindlimb[9] and diabetic cutaneous wound healing[10]. These data support the development of WKYMVm as a novel and effective anti-inflammatory therapeutic agent. In this study, we investigated the therapeutic efficacy of the FPR2 agonist WKYMVm in attenuating hyperoxia-induced lung inflammation and ensuing lung injuries, including impaired alveolarization and angiogenesis in newborn mice
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