No abstract

Mechanical ventilation of patients can be a life-saving treatment, but also imposes additional stress on the lung. Mitogen-activated protein kinases (MAPK) represent a family of protein kinases that become phosphorylated and activated by many different forms of stress.Using Western blot analysis, the present study analysed the effects of high distending pressure ventilation on the activation of the MAPK extracellular signal-related kinases (ERK)-1/2, c-Jun amino-terminal kinases (JNK) and p38 kinase, and on the MAPKactivated transcription factors c-Jun, ETS-like protein (Elk)-1 and activating transcription factor (ATF)-2.In adult rats, ventilation with high pressure (45/10 peak inspiratory pressure/positive end-expiratory pressure in cmH 2 O) for 30 or 60 min did not affect arterial oxygenation, but resulted in enhanced phosphorylation of ERK-1/2, JNK, c-Jun, Elk-1 and ATF-2 compared to normally ventilated (13/3) rats. The activation of ERK-1/2 and JNK was located to cells resembling alveolar type II cells. In addition, high pressure ventilation enhanced phosphorylation of the inhibitor of nuclear factor (NF)-kB and nuclear translocation of the transcription factor NF-kB. In isolated perfused mouse lungs, the MAPK/ERK kinase inhibitor U0126 prevented ventilation-induced activation of ERK-1/2 and Elk-1, but had no effect on ventilation-induced cytokine release.The present authors conclude that mechanical ventilation triggers specific signalling pathways, such as the mitogen-activated protein kinase and the nuclear factor-kB pathways, which may contribute to pulmonary inflammation and proliferation. Eur Respir J 2002; 20: 946-956.

/ ajplung.00478.2001.-The uptake of fluorescent-labeled liposomes (with a surfactant-like composition) by alveolar macrophages and alveolar type II cells was studied using flow cytometry, in vivo by instillation of the labeled liposomes in the trachea of ventilated rats followed by isolation of the alveolar cells and determination of the cell-associated fluorescence, and in vitro by incubation of isolated alveolar cells with the fluorescent liposomes. The results show that the uptake of liposomes by the alveolar cells is time and concentration dependent. In vivo alveolar macrophages internalize more than three times as many liposomes as alveolar type II cells, whereas in vitro, the amount of internalized liposomes by these cells is approximately the same. In vitro, practically all the cells (70-75%) internalize liposomes, whereas in vivo only 30% of the alveolar type II cells ingest liposomes vs. 70% of the alveolar macrophages. These results indicate that in vivo, only a small subpopulation of alveolar type II cells is able to internalize surfactant liposomes. pneumocyte; lung; liposome; fluorescence PULMONARY SURFACTANT lines the alveolar capillary membrane and plays an essential role in normal lung function. It is a complex of lipids and proteins synthesized by alveolar type II cells and is stored in lamellar bodies until it is secreted into the alveolar space (4). Within the alveolus, surfactant transforms to tubular myelin, which unfolds, and the surfactant lipids are rapidly inserted in the lipid monolayer present at the air-liquid interface (4). During a breathing cycle, lipids are squeezed out of the monolayer. To maintain the primary function of the monolayer, i.e., reduction of the surface tension, the loss of lipids from the monolayer has to be compensated by renewed insertion of lipids. Because the de novo synthesis of surfactant is insufficient to correct the natural loss (i.e., inactivation of surfactant), the alveolar type II cell not only produces newly synthesized surfactant but also reutilizes inactivated surfactant, derived from the alveolar space.The recycling of surfactant is a major pathway for surfactant in the alveolar space (14). Clearance by the mucociliary pathway (20) or degradation by alveolar type II cells and alveolar macrophages appears to be less important in the removal of surfactant lipids from the alveolar space.One important factor in the complex system of surfactant synthesis, secretion, recycling, clearing, and degradation is the uptake of surfactant lipids by alveolar type II cells and alveolar macrophages. Numerous in vitro studies have demonstrated that both cell types can internalize surfactant lipids, although their relative contribution in the uptake of surfactant lipids in the lung remains obscure. According to Miles et al. (11), based on in vitro studies, alveolar macrophages may be responsible for all the catabolism of surfactant lipids.In contrast, results of in vivo experiments suggest a primary role of alveolar type II cells in the uptake of surfactant lipids r...

The uptake of different surfactant lipids-dipalmitoylphosphatidylcholine (DPPC), phosphatidylglycerol (PG), or phosphatidylinositol (PI)-and liposomes with a surfactant-like composition by alveolar type II cells (alveolar type II cells) and macrophages (alveolar macrophages) was studied in vitro. Fluorescent-labeled liposomes containing either 86% of the studied lipid, i.e., DPPC, PG, PI, and 6% labeled phosphatidylethanolamine (PE) and 8% cholesterol or a lipid mixture similar to surfactant (DPPC, PG, PI, phosphatidylcholine, PE, and cholesterol in a weight ratio of 55:8:2:21:8:6) were incubated with alveolar macrophages and alveolar type II cells. The cell-associated fluorescence assessed by flow cytometry demonstrated a higher uptake of PG and PI by both alveolar macrophages and alveolar type II cells, and a lower uptake of DPPC by alveolar macrophages. In addition, fewer alveolar type II cells take up DPPC, whereas there are no differences for the alveolar macrophages in the number of cells involved in the uptake. Competition experiments with Texas Red-labeled liposomes and either DPPC liposomes or PI liposomes labeled with Bodipy indicated that all these liposomes are internalized via the same pathway by alveolar cells. Thus, lipid composition directly influences the (re)uptake of surfactant.

Here, we describe the development of a Dutch national guideline on metastases and hematological malignancies localized within the spine. The aim was to create a comprehensive guideline focusing on proactive management of these diseases, enabling healthcare professionals to weigh patient perspectives, life expectancy, and expected outcomes to make informed treatment recommendations. A national multidisciplinary panel consisting of clinicians, a nurse, a patient advocate, an epidemiologist, and a methodologist drafted the guideline. The important role of patients in the realization of the guideline enabled us to identify and address perceived shortcomings in patient care. The guideline covers not only metastatic epidural spinal cord compression, but also the treatment of uncomplicated metastases and hematological malignancies localized within the spine. The guideline is applicable in daily practice and provides an up-to-date and concise overview of the diagnostic and treatment possibilities for patients suffering from a disease that can have a serious impact on their quality of life. Suggestions for the practical implementation of patient care in hospitals are also provided, including approaches for pursuing proactive management. The crucial role of the patient in decision making is emphasized in this guideline.