Mechanisms of glucocorticoid insensitivity in asthma

Asthma and COPD are obstructive pulmonary diseases, which can be treated with anti-inflammatory drugs like glucocorticoids. This thesis aimed to investigate the circumstances which made that these glucocorticoids sometimes do not work like they should. We started by looking which factors predicted whether a subject with asthma would react properly to glucocorticoids. This study showed that some factor associated with eosinophilic inflammation was associated with a better response to glucocorticoid, unlike a more neutrophilic inflammation. Afterwards, we investigated possible mechanisms which could play role. Firstly, we determined that Interleukin-17A reduced the sensitivity of pulmonary epithelial cells to glucocorticoids. Therefore, the attraction of neutrophils remained present for a longer period. We showed the mechanism through which this occurred, which could be a target for future therapies in glucocorticoid insensitive disease. Th17 cells are one of the celltypes producing IL-17A and they are attracted by the protein CCL20. Therefore, we investigated the effect of glucocorticoids on CCL20 production. We found that glucocorticoids enhance the amount of CCL20 released by pulmonary epithelial cells. Possibly, this leads to a larger influx of Th17 cells in the lung. Furthermore we studied the effect of the damage that cigarette smoke does on inflammation. We found that the cell death caused by cigarette smoke leads to the release of molecules which can promote inflammation. The inhibition of a certain type of cell death, necroptosis, lead to the presence of less inflammatory cells in the lungs of mice after cigarette smoke exposition

Intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients:A narrative review of past, present, and future steps

BACKGROUND AND OBJECTIVE: Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. In this narrative review, we aim to provide a comprehensive overview of current insights into intra-abdominal pressure monitoring, intra-abdominal hypertension, and abdominal compartment syndrome. The focus of this review is on the pathophysiology, risk factors and outcome of intra-abdominal hypertension and abdominal compartment syndrome, and on therapeutic strategies, such as non-operative management, surgical decompression, and management of the open abdomen. Finally, future steps are discussed, including propositions of what a future guideline should focus on. CONCLUSIONS: Pathological intra-abdominal pressure is a continuum ranging from mild intra-abdominal pressure elevation without clinically significant adverse effects to substantial increase in intra-abdominal pressure with serious consequences to all organ systems. Intra-abdominal pressure monitoring should be performed in all patients at risk of intra-abdominal hypertension. Although continuous intra-abdominal pressure monitoring is feasible, this is currently not standard practice. There are a number of effective non-operative medical interventions that may be performed early in the patient's course to reduce intra-abdominal pressure and decrease the need for surgical decompression. Abdominal decompression can be life-saving when abdominal compartment syndrome is refractory to non-operative treatment and should be performed expeditiously. The objectives of open abdomen management are to prevent fistula and to achieve delayed fascial closure at the earliest possible time. There is still a lot to learn and change. The 2013 World Society of Abdominal Compartment Syndrome guidelines should be updated and multicentre studies should evaluate the effect of intra-abdominal hypertension treatment on patient outcome

Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury

Endothelial cells in the kidney microvasculature have an intrinsic molecular and phenotypic heterogeneity and respond to sepsis-induced acute kidney injury conditions in a segment-specific manner. This Review discusses the roles of these cells and the molecular systems that control endothelial functions in the development of sepsis-induced acute kidney injury. Microvascular endothelial cells in the kidney have been a neglected cell type in sepsis-induced acute kidney injury (sepsis-AKI) research; yet, they offer tremendous potential as pharmacological targets. As endothelial cells in distinct cortical microvascular segments are highly heterogeneous, this Review focuses on endothelial cells in their anatomical niche. In animal models of sepsis-AKI, reduced glomerular blood flow has been attributed to inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, whereas decreased cortex peritubular capillary perfusion is associated with epithelial redox stress. Elevated systemic levels of vascular endothelial growth factor, reduced levels of circulating sphingosine 1-phosphate and loss of components of the glycocalyx from glomerular endothelial cells lead to increased microvascular permeability. Although coagulation disbalance occurs in all microvascular segments, the molecules involved differ between segments. Induction of the expression of adhesion molecules and leukocyte recruitment also occurs in a heterogeneous manner. Evidence of similar endothelial cell responses has been found in kidney and blood samples from patients with sepsis. Comprehensive studies are needed to investigate the relationships between segment-specific changes in the microvasculature and kidney function loss in sepsis-AKI. The application of omics technologies to kidney tissues from animals and patients will be key in identifying these relationships and in developing novel therapeutics for sepsis