The acute respiratory distress syndrome in 2013.

Acute lung injury and the acute respiratory distress syndrome are major causes of morbidity and mortality in critically ill patients. This review focuses on new developments in definitions, epidemiology, clinical and basic research, and promising new directions in treatment. There is new information about the potential contribution of environmental factors, especially exposure to cigarette smoke. Pathologic findings in ARDS have been limited to case reports of open lung biopsies and post-mortem studies but there is some new information from a recent pathology study relative to the frequency of diffuse alveolar damage and the severity of arterial hypoxemia. Further, therapy with lung-protective ventilation and fluid conservative protocol has improved outcomes, but several new trials are in progress to test several promising strategies

Role of Aquaporin-4 in Airspace-to-Capillary Water Permeability in Intact Mouse Lung Measured by a Novel Gravimetric Method

The mammalian peripheral lung contains at least three aquaporin (AQP) water channels: AQP1 in microvascular endothelia, AQP4 in airway epithelia, and AQP5 in alveolar epithelia. In this study, we determined the role of AQP4 in airspace-to-capillary water transport by comparing water permeability in wild-type mice and transgenic null mice lacking AQP1, AQP4, or AQP1/AQP4 together. An apparatus was constructed to measure lung weight continuously during pulmonary artery perfusion of isolated mouse lungs. Osmotically induced water flux (Jv) between the airspace and capillary compartments was measured from the kinetics of lung weight change in saline-filled lungs in response to changes in perfusate osmolality. Jv in wild-type mice varied linearly with osmotic gradient size (4.4 × 10−5 cm3 s−1 mOsm−1) and was symmetric, independent of perfusate osmolyte size, weakly temperature dependent, and decreased 11-fold by AQP1 deletion. Transcapillary osmotic water permeability was greatly reduced by AQP1 deletion, as measured by the same method except that the airspace saline was replaced by an inert perfluorocarbon. Hydrostatically induced lung edema was characterized by lung weight changes in response to changes in pulmonary arterial inflow or pulmonary venous outflow pressure. At 5 cm H2O outflow pressure, the filtration coefficient was 4.7 cm3 s−1 mOsm−1 and reduced 1.4-fold by AQP1 deletion. To study the role of AQP4 in lung water transport, AQP1/AQP4 double knockout mice were generated by crossbreeding of AQP1 and AQP4 null mice. Jv were (cm3 s−1 mOsm−1 × 10−5, SEM, n = 7–12 mice): 3.8 ± 0.4 (wild type), 0.35 ± 0.02 (AQP1 null), 3.7 ± 0.4 (AQP4 null), and 0.25 ± 0.01 (AQP1/AQP4 null). The significant reduction in Pf in AQP1 vs. AQP1/AQP4 null mice was confirmed by an independent pleural surface fluorescence method showing a 1.6 ± 0.2-fold (SEM, five mice) reduced Pf in the AQP1/AQP4 double knockout mice vs. AQP1 null mice. These results establish a simple gravimetric method to quantify osmosis and filtration in intact mouse lung and provide direct evidence for a contribution of the distal airways to airspace-to-capillary water transport

Aquaporin-1 Deficiency Protects Against Myocardial Infarction by Reducing Both Edema and Apoptosis in Mice

Many studies have determined that AQP1 plays an important role in edema formation and resolution in various tissues via water transport across the cell membrane. The aim of this research was to determine both if and how AQP1 is associated with cardiac ischemic injury, particularly the development of edema following myocardial infarction (MI). AQP1+/+ and AQP1−/− mice were used to create the MI model. Under physiological conditions, AQP1−/− mice develop normally; however, in the setting of MI, they exhibit cardioprotective properties, as shown by reduced cardiac infarct size determined via NBT staining, improved cardiac function determined via left ventricular catheter measurements, decreased AQP1-dependent myocardial edema determined via water content assays and decreased apoptosis determined via TUNEL analysis. Cardiac ischemia caused by hypoxia secondary to AQP1 deficiency stabilized the expression of HIF-1α in endothelial cells and subsequently decreased microvascular permeability, resulting in the development of edema. The AQP1-dependent myocardial edema and apoptosis contributed to the development of MI. AQP1 deficiency protected cardiac function from ischemic injury following MI. Furthermore, AQP1 deficiency reduced microvascular permeability via the stabilization of HIF-1α levels in endothelial cells and decreased cellular apoptosis following MI

Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs

Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy

BackgroundImmune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance.Methods190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance.ResultsWe found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs.ConclusionPatients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance

Airway surface liquid depth imaged by surface laser reflectance microscopy

The thin layer of liquid at the surface of airway epithelium, the airway surface liquid (ASL), is important in normal airway physiology and in the pathophysiology of cystic fibrosis. At present, the best method to measure ASL depth involves scanning confocal microscopy after staining with an aqueous-phase fluorescent dye. We describe here a simple, noninvasive imaging method to measure ASL depth by reflectance imaging of an epithelial mucosa in which the surface is illuminated at a 45-degree angle by an elongated 13-µm wide rectangular beam produced by a 670-nm micro-focus laser. The principle of the method is that air–liquid, liquid–liquid, and liquid–cell interfaces produce distinct specular or diffuse reflections that can be imaged to give a micron-resolution replica of the mucosal surface. The method was validated using fluid layers of specified thicknesses and applied to measure ASL depth in cell cultures and ex vivo fragments of pig trachea. In addition, the method was adapted to measure transepithelial fluid transport from the dynamics of fluid layer depth. Compared with confocal imaging, ASL depth measurement by surface laser reflectance microscopy does not require dye staining or costly instrumentation, and can potentially be adapted for in vivo measurements using fiberoptics

Role of Aquaporin Water Channels in Airway Fluid Transport, Humidification, and Surface Liquid Hydration

Several aquaporin-type water channels are expressed in mammalian airways and lung: AQP1 in microvascular endothelia, AQP3 in upper airway epithelia, AQP4 in upper and lower airway epithelia, and AQP5 in alveolar epithelia. Novel quantitative methods were developed to compare airway fluid transport–related functions in wild-type mice and knockout mice deficient in these aquaporins. Lower airway humidification, measured from the moisture content of expired air during mechanical ventilation with dry air through a tracheotomy, was 54–56% efficient in wild-type mice, and reduced by only 3–4% in AQP1/AQP5 or AQP3/AQP4 double knockout mice. Upper airway humidification, measured from the moisture gained by dry air passed through the upper airways in mice breathing through a tracheotomy, decreased from 91 to 50% with increasing ventilation from 20 to 220 ml/min, and reduced by 3–5% in AQP3/AQP4 knockout mice. The depth and salt concentration of the airway surface liquid in trachea was measured in vivo using fluorescent probes and confocal and ratio imaging microscopy. Airway surface liquid depth was 45 ± 5 μm and [Na+] was 115 ± 4 mM in wild-type mice, and not significantly different in AQP3/AQP4 knockout mice. Osmotic water permeability in upper airways, measured by an in vivo instillation/sample method, was reduced by ∼40% by AQP3/AQP4 deletion. In doing these measurements, we discovered a novel amiloride-sensitive isosmolar fluid absorption process in upper airways (13% in 5 min) that was not affected by aquaporin deletion. These results establish the fluid transporting properties of mouse airways, and indicate that aquaporins play at most a minor role in airway humidification, ASL hydration, and isosmolar fluid absorption