Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies

Abstract Background Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. Main body Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. Conclusion Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem

Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury.

Notch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury