Bronchopulmonary dysplasia is the most common complication when premature birth occurs at less than 28 weeks gestational age. The general aim of this thesis is to explore the therapeutic... Show moreBronchopulmonary dysplasia is the most common complication when premature birth occurs at less than 28 weeks gestational age. The general aim of this thesis is to explore the therapeutic potential of interventions in signaling pathways, involved in lung development and oxidative stress-induced lung injury, to prevent or attenuate BPD in a neonatal rat model, in which experimental BPD is induced by exposure to hyperoxia. The therapeutic potential of the targeting compounds of signaling pathways was investigated by studying their beneficial effects on contributing factors to severe experimental BPD pathology, including aberrant alveolar and vascular development, inflammation, fibrosis, coagulation, vascular remodeling, pulmonary arterial hypertension and right ventricular hypertrophy. We found ⑴angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats; ⑵ Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response; ⑶ Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats; ⑷Adult lysophosphatidic acid receptor 1-deficient rats with hyperoxia-induced neonatal chronic lung disease are protected against lipopolysaccharide-induced acute lung injury; ⑸ Bone morphogenetic protein 9 protects against neonatal hyperoxia-induced impairment of alveolarization and pulmonary inflammation. Show less
Due to a lack of patient materials and ethical reasons animal models of BPD are critical for characterization the pathophysiology of BPD and testing of potential treatment options. In chapter 2 of... Show moreDue to a lack of patient materials and ethical reasons animal models of BPD are critical for characterization the pathophysiology of BPD and testing of potential treatment options. In chapter 2 of this thesis we characterize a rat model for experimental BPD, induced in neonatal pups by prolonged exposure to hyperoxia, by investigating histopathology and differential gene expression profiles in the lung and demonstrate its significance for studying BPD in premature infants. In chapter 3 we describe the spatial and temporal expression of surfactant proteins in this experimental BPD model. Since inflammation and unbalanced coagulation and fibrinolysis, leading to extravascular fibrin deposition in the lung, are two interrelated processes that play a pivotal role in the pathophysiology of inflammatory lung disease, we investigated whether the pathophysiology of experimental BPD could be improved by interrupting the vicious cycle of inflammation and coagulation. Fibrin deposition can be prevented directly via inhibition of the coagulation cascade and/or stimulation of the fibrinolytic cascade or indirectly via inhibition of the inflammatory response, thereby preventing activated leucocytes to perform their procoagulant and antifibrinolytic activity. In chapters 4 and 5 intervention studies in experimental BPD are described which study the potential therapeutic effect of agents with anti-inflammatory and/or anticoagulant activity for premature infants who are at risk of developing BPD. The role of pentoxifylline, a methylxantine derivative and weak non-selective phosphodiesterase inhibitor with anti-inflammatory and anticoagulant properties, and with positive effects on capillary blood flow in experimental BPD is presented in chapter 4. The role of nitric oxide, a gas that is involved in multiple (patho)physiological processes in the injured lung, including pulmonary vasodilatation, inflammation and plasma exudation, is presented in chapter 5. In chapter 6 the presented studies of chapters 2-5 and the future perspectives are discussed. In chapter 7 a summary is given of this thesis. Due to a lack of patient materials and ethical reasons animal models of BPD are critical for characterization the pathophysiology of BPD and testing of potential treatment options. In chapter 2 of this thesis we characterize a rat model for experimental BPD, induced in neonatal pups by prolonged exposure to hyperoxia, by investigating histopathology and differential gene expression profiles in the lung and demonstrate its significance for studying BPD in premature infants. In chapter 3 we describe the spatial and temporal expression of surfactant proteins in this experimental BPD model. Since inflammation and unbalanced coagulation and fibrinolysis, leading to extravascular fibrin deposition in the lung, are two interrelated processes that play a pivotal role in the pathophysiology of inflammatory lung disease, we investigated whether the pathophysiology of experimental BPD could be improved by interrupting the vicious cycle of inflammation and coagulation. Fibrin deposition can be prevented directly via inhibition of the coagulation cascade and/or stimulation of the fibrinolytic cascade or indirectly via inhibition of the inflammatory response, thereby preventing activated leucocytes to perform their procoagulant and antifibrinolytic activity. In chapters 4 and 5 intervention studies in experimental BPD are described which study the potential therapeutic effect of agents with anti-inflammatory and/or anticoagulant activity for premature infants who are at risk of developing BPD. The role of pentoxifylline, a methylxantine derivative and weak non-selective phosphodiesterase inhibitor with anti-inflammatory and anticoagulant properties, and with positive effects on capillary blood flow in experimental BPD is presented in chapter 4. The role of nitric oxide, a gas that is involved in multiple (patho)physiological processes in the injured lung, including pulmonary vasodilatation, inflammation and plasma exudation, is presented in chapter 5. In chapter 6 the presented studies of chapters 2-5 and the future perspectives are discussed. In chapter 7 a summary is given of this thesis. Due to a lack of patient materials and ethical reasons animal models of BPD are critical for characterization the pathophysiology of BPD and testing of potential treatment options. In chapter 2 of this thesis we characterize a rat model for experimental BPD, induced in neonatal pups by prolonged exposure to hyperoxia, by investigating histopathology and differential gene expression profiles in the lung and demonstrate its significance for studying BPD in premature infants. In chapter 3 we describe the spatial and temporal expression of surfactant proteins in this experimental BPD model. Since inflammation and unbalanced coagulation and fibrinolysis, leading to extravascular fibrin deposition in the lung, are two interrelated processes that play a pivotal role in the pathophysiology of inflammatory lung disease, we investigated whether the pathophysiology of experimental BPD could be improved by interrupting the vicious cycle of inflammation and coagulation. Fibrin deposition can be prevented directly via inhibition of the coagulation cascade and/or stimulation of the fibrinolytic cascade or indirectly via inhibition of the inflammatory response, thereby preventing activated leucocytes to perform their procoagulant and antifibrinolytic activity. In chapters 4 and 5 intervention studies in experimental BPD are described which study the potential therapeutic effect of agents with anti-inflammatory and/or anticoagulant activity for premature infants who are at risk of developing BPD. The role of pentoxifylline, a methylxantine derivative and weak non-selective phosphodiesterase inhibitor with anti-inflammatory and anticoagulant properties, and with positive effects on capillary blood flow in experimental BPD is presented in chapter 4. The role of nitric oxide, a gas that is involved in multiple (patho)physiological processes in the injured lung, including pulmonary vasodilatation, inflammation and plasma exudation, is presented in chapter 5. In chapter 6 the presented studies of chapters 2-5 and the future perspectives are discussed. In chapter 7 a summary is given of this thesis. Due to a lack of patient materials and ethical reasons animal models of BPD are critical for characterization the pathophysiology of BPD and testing of potential treatment options. In chapter 2 of this thesis we characterize a rat model for experimental BPD, induced in neonatal pups by prolonged exposure to hyperoxia, by investigating histopathology and differential gene expression profiles in the lung and demonstrate its significance for studying BPD in premature infants. In chapter 3 we describe the spatial and temporal expression of surfactant proteins in this experimental BPD model. Since inflammation and unbalanced coagulation and fibrinolysis, leading to extravascular fibrin deposition in the lung, are two interrelated processes that play a pivotal role in the pathophysiology of inflammatory lung disease, we investigated whether the pathophysiology of experimental BPD could be improved by interrupting the vicious cycle of inflammation and coagulation. Fibrin deposition can be prevented directly via inhibition of the coagulation cascade and/or stimulation of the fibrinolytic cascade or indirectly via inhibition of the inflammatory response, thereby preventing activated leucocytes to perform their procoagulant and antifibrinolytic activity. In chapters 4 and 5 intervention studies in experimental BPD are described which study the potential therapeutic effect of agents with anti-inflammatory and/or anticoagulant activity for premature infants who are at risk of developing BPD. The role of pentoxifylline, a methylxantine derivative and weak non-selective phosphodiesterase inhibitor with anti-inflammatory and anticoagulant properties, and with positive effects on capillary blood flow in experimental BPD is presented in chapter 4. The role of nitric oxide, a gas that is involved in multiple (patho)physiological processes in the injured lung, including pulmonary vasodilatation, inflammation and plasma exudation, is presented in chapter 5. In chapter 6 the presented studies of chapters 2-5 and the future perspectives are discussed. In chapter 7 a summary is given of this thesis. Show less
