Alveolar Capillaries Research Articles

Metastasis-Associated Protein 1 Deficiency Results in Compromised Pulmonary Alveolar Capillary Angiogenesis in Mice.

BackgroundThe aim of this study was to investigate the effects of metastasis-associated protein 1 (MTA1) deficiency during angiogenesis of pulmonary alveolar capillaries in mice and to determine the molecular mechanisms involved.Material/MethodsThe expressions of MTA1, CD34, vascular endothelial growth factor (VEGF), alpha smooth muscle actin (α-SMA), and HIF-1α were analyzed in the lungs of MTA1-knockout (KO) and wild-type mice at embryonic day 18.5 and 2 months by quantitative PCR, immunoblotting, and immunohistochemistry. The morphological changes were investigated during pulmonary alveolar capillary formation. The heart weight/body weight (HW/BW) ratio and the size of the right ventricular wall cardiomyocytes were also measured. Regulation of MTA1 on HIF-1α was determined in vitro.ResultsMTA1 deficiency reduced the number of pulmonary alveolar capillaries compared to the wild-type mice. MTA1-KO mice exhibited a decreased expression of HIF-1α and VEGF in the lungs. The retarded growth of the MTA1-KO mice was also noticed during the first week after birth. Accordingly, MTA1 deficiency resulted in increased infant mortality. In surviving adult mice, MTA1 deficiency induced myocardial hypertrophy, highlighted by an increased heart weight/body weight ratio and larger cardiomyocytes. In cultured cells, HIF-1α and VEGF levels were significantly upregulated upon MTA1 overexpression, suggesting a close relationship between all 3 molecules.ConclusionsMTA1 participates in the formation of pulmonary capillaries via stabilization of HIF-1α. This finding sheds new light on the function of MTA1 in lung development, opening new avenues for the diagnosis/treatment of related pulmonary diseases.

Abstract 4803: Over-production of thrombopoietin in the liver of transgenic mice with liver-specific human BrafV600E expression

Abstract The BrafV637E mutation, which corresponds to the human BRAFV600E mutation, plays a pivotal role in mouse hepatic carcinogenesis induced by neonatal treatment with diethylnitrosamine in B6C3F1 mice. We previously established the transgenic mice that express the human BRAFV600E mutation in the liver (Mol Carcinog 2016. doi:10.1002/mc22510). The transgenic mice showed 5 folds increase in liver/body weight as compared to normal mice, and their liver was entirely consisted of small basophilic hepatocytes resembling DEN-induced preneoplastic hepatocytes. The transgenic mice were normally born, but most of them spontaneously died during 2-3 months after birth. In this study, we investigated the reason for spontaneous death in the liver-specific BRAFV600E transgenic mice. The numbers of platelets and megakaryocytes were remarkably increased respectively in peripheral blood and bone marrow in the transgenic mice. Furthermore, fragmented red blood cells and activated platelets with enlarged size were frequently observed in the peripheral blood smear of the transgenic mice. Thrombopoietin mRNA was abundantly expressed in the liver of transgenic mice, and the conditioned-medium of the cultured hepatocytes from the transgenic mice contained increased amount of thrombopoietin as compared with that of normal mouse hepatocytes. Histopathological analysis revealed that many platelets were adhered to the sinusoidal walls in the liver of the transgenic mice. Furthermore, glomerulonephritis associating with platelet deposition in glomerular capillaries and interstitial pneumonia accompanying microthrombosis in alveolar capillaries were also observed. Because platelets have been shown to promote liver regeneration through interaction with various hepatic cell components such as hepatocytes, endothelial cells and Kupffer cells, the platelet accumulation in the liver of the transgenic mice may represent the stimulation for growth and proliferation of hepatocytes by platelets. On the other hand, the platelets might cause the renal and pulmonary diseases which might cause spontaneous death in these mice. Our results indicate that over-production of thrombopoietin by the BRAF-mutated hepatocytes may create the macroenvironment that may favor the growth and proliferation of neoplastic hepatocytes.(Supported by the grant from Japanese Ministry of Education, Culture, Sports, Science and Technology.) Citation Format: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Katsuhiro Okuda, Masaru Asari, Katsuhiro Okuda, Seiji Ohtani, Kosuke Yamazaki, Keiko Shimizu, Katsuhiro Ogawa. Over-production of thrombopoietin in the liver of transgenic mice with liver-specific human BrafV600E expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4803. doi:10.1158/1538-7445.AM2017-4803

An autopsy case of non‐traumatic fat embolism syndrome

Fat embolism syndrome (FES) occurs after long bone fractures and the symptoms appear 24-72 h after the initial trauma. Fat emboli can affect both the pulmonary and systemic circulation. Apart from the most common type of FES that originates from bone fracture, non-traumatic FES has been also reported. We have experienced an autopsy case of non-traumatic FES. An 81-year-old man with hepatocellular carcinoma associated with alcoholic liver cirrhosis suddenly lost consciousness before transcatheter arterial chemoembolization treatment for his disease and died 5 h after the episode. At autopsy, numerous fat droplets were detected in the alveolar capillaries of the lung and glomerular capillaries of the kidney. Lipid analysis of lung autopsy specimens by thin-layer chromatography showed that the emboli were composed mainly of tristearin. Free fatty acids (FFA) has been considered to be the main component of fat emboli and can be a cause of acute respiratory distress syndrome (ARDS). However, in the present case, the lung specimen contained tristearin and ARDS did not occur. This is the first report of non-traumatic FES in which lipid analysis of human autopsy specimens has been conducted.

Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial–mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow-derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial–mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 μm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-β signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-β signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF.

Red blood cell dynamics in biomimetic microfluidic networks of pulmonary alveolar capillaries.

The pulmonary capillary networks (PCNs) embody organ-specific microvasculatures, where blood vessels form dense meshes that maximize the surface area available for gas exchange in the lungs. With characteristic capillary lengths and diameters similar to the size of red blood cells (RBCs), seminal descriptions coined the term "sheet flow" nearly half a century ago to differentiate PCNs from the usual notion of Poiseuille flow in long straight tubes. Here, we revisit in true-scale experiments the original “sheet flow” model and devise for the first time biomimetic microfluidic platforms of organ-specific PCN structures perfused with RBC suspensions at near-physiological hematocrit levels. By implementing RBC tracking velocimetry, our measurements reveal a wide range of heterogonous RBC pathways that coexist synchronously within the PCN; a phenomenon that persists across the broad range of pressure drops and capillary segment sizes investigated. Interestingly, in spite of the intrinsic complexity of the PCN structure and the heterogeneity in RBC dynamics observed at the microscale, the macroscale bulk flow rate versus pressure drop relationship retains its linearity, where the hydrodynamic resistance of the PCN is to a first order captured by the characteristic capillary segment size. To the best of our knowledge, our in vitro efforts constitute a first, yet significant, step in exploring systematically the transport dynamics of blood in morphologically inspired capillary networks.

Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.

Anti‐angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti‐angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre‐existing vessels from surrounding tissue (vessel co‐option). As anti‐angiogenic therapies were designed to target only new blood vessel growth, vessel co‐option has been proposed as a mechanism that could drive resistance to anti‐angiogenic therapy. However, vessel co‐option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti‐angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co‐option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co‐opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co‐opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co‐option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co‐option mediates resistance to the anti‐angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co‐option in lung metastases occurs through at least three distinct mechanisms, that vessel co‐option occurs frequently in lung metastases, and that vessel co‐option could mediate resistance to anti‐angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co‐option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Lung morphometry: the link between structure and function.

The study of the structural basis of gas exchange function in the lung depends on the availability of quantitative information that concerns the structures establishing contact between the air in the alveoli and the blood in the alveolar capillaries, which can be entered into physiological equations for predicting oxygen uptake. This information is provided by morphometric studies involving stereological methods and allows estimates of the pulmonary diffusing capacity of the human lung that agree, in experimental studies, with the maximal oxygen consumption. The basis for this "machine lung" structure lies in the complex design of the cells building an extensive air-blood barrier with minimal cell mass.

Pathognomonic remodeling of blood and lymphatic capillaries in idiopathic pulmonary fibrosis.

Numerous studies have been published investigating the pathologic alterations in various interstitial pneumonias, particularly in idiopathic pulmonary fibrosis (IPF). However, the few existing studies on capillary remodeling, which does not seem to have priority for pathologic diagnosis, are contradictory, with some reporting increased and others reduced vascularization. We hypothesized that these discrepancies were due to the temporal heterogeneity of the lesions in IPF. We subsequently developed original techniques for evaluating vascular density within the alveolar septa and discovered, for the first time, a heterogeneous increase in alveolar capillaries in the lungs of IPF patients. Notably, we consistently found that the fibrotic lesions in IPF lungs, which are composed mainly of dense collagen with myofibroblasts, featured a reduction in capillaries. This finding provides a plausible explanation for the intractability of IPF, as this reduced vascularization would result in poor delivery of anti-fibrotic agents to these lesions. We also reported the disappearance of subpleural and interlobular lymphatics in IPF lungs, which likely results in poor alveolar clearance in the diseased lungs. Finally, we assessed the autopsied lungs of patients with IPF who died because of acute exacerbation and observed increased and dilated alveolar capillaries. These capillaries are likely to be "leaky" owing to exposure to VEGF produced by regenerated alveolar type II epithelial cells. Furthermore, poor alveolar clearance may prolong the high mobility group box 1 (HMGB1)-induced lung injury in acute exacerbation of IPF. Our data obtained from the assessment of blood and lymphatic capillary alterations in IPF provide novel pathogenetic insights and may provide the basis for new therapeutic strategies targeting IPF.

Physical sequestration of Bacillus anthracis in the pulmonary capillaries in terminal infection

Mice are exquisitely sensitive to infection with encapsulated B. anthracis strains, even in the absence of toxins. Bioluminescence imaging shows that the lungs are the terminals targets before death, whatever the route of infection: cutaneous, inhalational or digestive. In this study, we addressed the pathophysiological mechanisms of this phenomenon during a cutaneous infection in the absence of toxins. Ultrastructural analysis before the appearance of any clinical signs shows a high density of encapsulated bacteria colonizing the alveolar capillary network. Histological analysis when clinical signs were patent, just before death, showed lung tissue damage, with bacteria localized in alveolar capillaries and spaces along alveolar cells. Bronchiolar epithelium injury and intra-alveolar hemorrhages were also observed. Using functional approaches, we detected hypoxia of blood vessel endothelial cells in the lung, and multifocal hypoxic zones in the brain parenchyma, associated with neurological signs at the time of death. During the bacteriemic phase of infection, we determined that the bacteria circulating in blood presented as chains of circa 13 μm in length with a mean of 4 bacteria per chain. To address the mechanisms of lung colonization, we mimicked this phase of infection by intravenous inoculation of bioluminescent bacteria of a similar chain length; the bacteria were immediately trapped within the lung capillary network. Encapsulated bacteria of shorter length were not sequestered and trapping was decreased in the absence of the capsule surrounding the bacilli. In conclusion, we show that the high pathogenicity of B. anthracis in the absence of toxins is most probably linked to physical sequestration of blood-circulating encapsulated bacilli of a given length. Clearly, in the case of anthrax, the toxins produced by the trapped encapsulated B. anthracis will add locally their deleterious effects. Controlling the lung-targeted pathology would be beneficial for the prognosis of anthrax infection.

Perfusion-related stimuli for compensatory lung growth following pneumonectomy.

Following pneumonectomy (PNX), two separate mechanical forces act on the remaining lung: parenchymal stress caused by lung expansion, and microvascular distension and shear caused by increased perfusion. We previously showed that parenchymal stress and strain explain approximately one-half of overall compensation; the remainder was presumptively attributed to perfusion-related factors. In this study, we directly tested the hypothesis that perturbation of regional pulmonary perfusion modulates post-PNX lung growth. Adult canines underwent banding of the pulmonary artery (PAB) to the left caudal (LCa) lobe, which caused a reduction in basal perfusion to LCa lobe without preventing the subsequent increase in its perfusion following right PNX while simultaneously exaggerating the post-PNX increase in perfusion to the unbanded lobes, thereby creating differential perfusion changes between banded and unbanded lobes. Control animals underwent sham pulmonary artery banding followed by right PNX. Pulmonary function, regional pulmonary perfusion, and high-resolution computed tomography of the chest were analyzed pre-PNX and 3-mo post-PNX. Terminally, the remaining lobes were fixed for detailed morphometric analysis. Results were compared with corresponding lobes in two control (Sham banding and normal unoperated) groups. PAB impaired the indices of post-PNX extravascular alveolar tissue growth by up to 50% in all remaining lobes. PAB enhanced the expected post-PNX increase in alveolar capillary formation, measured by the prevalence of double-capillary profiles, in both unbanded and banded lobes. We conclude that perfusion distribution provides major stimuli for post-PNX compensatory lung growth independent of the stimuli provided by lung expansion and parenchymal stress and strain.

Protective effect of Astragaloside IV against sepsis-induced acute lung injury in rats

The study aimed to explore the protective effects of AS-IV against sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) method in Sprague Dawley rats. Rats were randomly assigned into five groups: animals undergoing a sham CLP (sham group); animals undergoing CLP (CLP group); animals undergoing CLP and treated with AS-IV at 2.5mg/kgbw (low-dose AS-IV [L-AS] group), at 5mg/kgbw (mid-dose AS-IV [M-AS] group), and at 10mg/kgbw (high-dose AS-IV [H-AS] group). At 6h, 12h and 24h post-CLP surgery, six rats were respectively sacrificed to collect blood and lung tissue samples. The levels of arterial blood gas index, lung water content, protein level and leukocyte counts (total amount, neutrophils and lymphocytes) in bronchoalveolar lavage fluid (BALF) and cytokines such as TNF-α and IL-6 in BALF were measured at each time point in different groups. HE-staining and optical microscopy were performed to examine the pathological changes in lungs. The 72h-survival rate of each group was also recorded. PaO2 was decreased significantly, while the lung water content, BALF protein level, cell numbers, BALF cytokine TNF-α and IL-6 levels were increased significantly for CLP group as compared with sham group. Moreover, pathological injury was observed in lung tissue indicating the successful sepsis-induced ALI model. Speaking of the effect of AS-IV, we founded that, compared with the CLP group, the AS-IV treatment groups could significantly alleviate all the abovenegative changes exited in the CLP group in a dose-dependent manner. What’s more, the pathological injury was also gradually improved by AS-IV treatment compared with the CLP rats. AS-IV exerts its protective effect against sepsis-induced ALI in rats via improving pulmonary ventilation function, decreasing the permeability of alveolar epithelium and capillary as well as repressing lung inflammation.

Lung Inflammation and Pulmonary Intravascular Macrophage Recruitment in L‐Arginine‐Induced Acute Necrotizing Pancreatitis in Mouse

Human patients suffering from severe acute pancreatitis are at higher risk of developing acute lung injury with high morbidity and mortality rates. Although there are many studies on the mechanisms leading to acute lung injury associated with acute pancreatitis in experimental models, there has not been any investigation on the induction of pulmonary intravascular macrophages (PIMs), a pro‐inflammatory cell normally present in cattle, pig, and horses, during this pathological condition in animal models. Therefore, we tested the hypothesis that lungs from mice with L‐arginine‐induced acute necrotizing pancreatitis (ANP) will be inflamed along with the recruitment of PIMs, compared to lungs of control mice. ANP was induced in C57BL/6 mice by administering two intraperitoneal injections, one hour apart, of a sterile L‐arginine monohydrochloride 9% solution at the dose of 4.5g/kg per injection, and mice were euthanized at 24h (n=7), 72h (n=7) and 120h (n=7) post‐injections. Control mice (n=9) received the same injections but with physiological sterile saline. ANP was confirmed by a pathologist using a histological grading system for pancreatic necrosis, infiltration of inflammatory cells and edema, which generated total ANP severity scores as follows: median (with range) of 0 for controls, 1 (0–3) for the 24h group, 8 (6–10) for the 72h group and 4 (2–10) for the 120h group. Serum amylase was significantly increased in the 24h group (5528±1210 U/L) and the 72h group (6547±1275 U/L), but not in the 120h group (1399±62 U/L), compared to control (1483±48 U/L), p<0.001. The lung histological grading revealed infiltration of mononuclear phagocytes in the lungs of mice in the 72h group only, compared to the control lungs (p<0.001). Immunohistochemistry with anti‐macrophage CD‐68 antibody revealed an increase of monocytes/macrophages present in alveolar septa of the lungs of all mice with ANP, suggesting PIMs induction, compared with control mice (p<0.01), with cell counts (median; range) as follows: control mice (81; 55–147), 24h group (150; 115–190), 72h group (190; 118–200) and 120h group (135; 97–194). Bioplex assay on lung homogenates identified increased levels of IL‐6 (p < 0,0001), IL‐10 (p < 0,01), and MCP‐1 (p < 0,05) in the 24h group only, compared to control mice. Immunohistochemistry for vWF revealed granular staining in the alveolar septal capillaries of some ANP mice, but not in control mice, suggesting activation of the lung microvasculature endothelium during ANP. The data show that lung inflammation in mice with L‐arginine‐induced ANP is initiated as early as 24h and is characterised by the infiltration of septal mononuclear phagocytes, most probably PIMs, as well as by increased lung concentrations of IL‐6, IL‐10 and MCP‐1. Because of the established role of PIMs in lung inflammation, the mouse model of ANP will be a useful tool to investigate the biology of PIMs in ANP‐associated lung inflammation.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada

The transition to extra‐uterine life by extremely preterm infants – handle with care

The transition to extra‐uterine life by extremely preterm infants – handle with care

Increased c-kit and stem cell factor expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia

PurposePersistent pulmonary hypertension(PPH) in congenital diaphragmatic hernia (CDH) is caused by increased vascular cell proliferation and endothelial cell (EC) dysfunction, thus leading to obstructive changes in the pulmonary vasculature. C-Kit and its ligand, stem cell factor(SCF), are expressed by ECs in the developing lung mesenchyme, suggesting an important role during lung vascular formation. Conversely, absence of c-Kit expression has been demonstrated in ECs of dysplastic alveolar capillaries. We hypothesized that c-Kit and SCF expression is increased in the pulmonary vasculature of nitrofen-induced CDH. MethodsTimed-pregnant rats received nitrofen or vehicle on gestational day 9(D9). Fetuses were sacrificed on D15, D18, and D21, and divided into control and CDH group. Pulmonary gene expression levels of c-Kit and SCF were analyzed by qRT-PCR. Immunofluorescence double staining for c-Kit and SCF was combined with CD34 to evaluate protein expression in ECs of the pulmonary vasculature. ResultsRelative mRNA levels of c-Kit and SCF were significantly increased in lungs of CDH fetuses on D15, D18, and D21 compared to controls. Confocal laser scanning microscopy confirmed markedly increased vascular c-Kit and SCF expression in mesenchymal ECs of CDH lungs on D15, D18, and D21 compared to controls. ConclusionIncreased expression of c-Kit and SCF in the pulmonary vasculature of nitrofen-induced CDH lungs suggest that increased c-Kit signaling during lung vascular formation may contribute to vascular remodeling and thus to PPH.

Congenital diaphragmatic hernia in a crossbred piglet: A case report

Congenital diaphragmatic hernia (CDH) is a congenital defect affecting the diaphragm resulting in herniation of organs from abdominal cavity into thoracic cavity. It is a life-threatening condition and a major cause of death due to two complications: pulmonary hypoplasia and pulmonary hypertension. A stillborn male crossbred piglet on necropsy revealed hydrothorax and hydro-peritoneum. Thoracic cavity showed protrusion of parts of the small intestine into the cavity through the right side of the diaphragm, no hernial sac was detected and lungs were under-developed. Liver showed severe congestion and marked enlargement with abnormal lobulation. Cortical surface of both kidneys were rough and granular. Parallely placed double spleen with multiple hemorrhagic areas was noticed. Microscopic examination of kidney showed diffused cortical mononuclear cell infiltration with mild engorgement of medullary capillaries. In lungs, alveolar capillaries were moderately engorged with prominent interlobular septa and severe atelectasis. In liver, multifocal areas of hemorrhages and hydropic degeneration of hepatocytes was noticed. The case was diagnosed as congenital diaphragmatic hernia.

Algorithms of Relationships between Left Ventricle Dysfunction and Atrial Fibrillation

Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia. Many studies have investigated the cause for the development of AF in the left ventricle dysfunction. Recently the hypothesis was proposed that atrial fibrillation is a protective physiological mechanism, based on the termination of atrial mechanical systole. This reduces the enddiastolic pressure in the left ventricle by excluding the component of systolic left atrial pressure from the total enddiastolic pressure and, respectively, in the system of the pulmonary veins and alveolar capillaries in situation of the left ventricle dysfunction, and thus reduces the likelihood for development of pulmonary congestion. First of all this hypothesis explains relationship between left ventricle dysfunction and AF. The hypothesis helps to build algorithms of the development AF in the cases of the left ventricle dysfunction in the various diseases and conditions.

Incidental pulmonary trophoblastic embolism in a chinchilla

This case study presents the pathomorphological description of a pulmonary trophoblastic embolism in a female chinchilla, which died due to respiratory distress. Routine necropsy examination revealed the presence of multiple small and grey coloured foci, which presented with a hyperaemic and multifocal appearance on the surface of the lungs. Samples taken from the lung tissue were subjected to routine tissue processing and stained with haematoxylin-eosin (HE) and periodic acid-Schiff (PAS) reagents. Histopathological examination demonstrated one or more giant cells with rather large nuclei and a broad cytoplasm in the alveolar capillaries, which appeared as multifocal areas. These cellular structures were positive for PAS staining. And also, lymphocytic and histiocytic inflammatory cells infiltration were observed around the alveoli and bronchi-bronchioles

αKlotho deficiency in acute kidney injury contributes to lung damage.

αKlotho is a circulating protein that originates predominantly from the kidney and exerts cytoprotective effects in distant sites. We previously showed in rodents that the lung is particularly vulnerable to αKlotho deficiency. Because acute lung injury is a common and serious complication of acute kidney injury (AKI), we hypothesized that αKlotho deficiency in AKI contributes to lung injury. To test the hypothesis, we created AKI by renal artery ischemia-reperfusion in rats and observed the development of alveolar interstitial edema and increased pulmonary oxidative damage to DNA, protein, and lipids. Administration of αKlotho-containing conditioned media 6 h post-AKI did not alter plasma creatinine but improved recovery of endogenous αKlotho production 3 days post-AKI, reduced lung edema and oxidative damage, and increased endogenous antioxidative capacity in the lung. Intravenously injected αKlotho rapidly exits alveolar capillaries as a macromolecule, suggesting transcytosis and direct access to the epithelium. To explore the epithelial action of αKlotho, we simulated oxidative stress in vitro by adding hydrogen peroxide to cultured A549 lung epithelial cells. Purified recombinant αKlotho directly protected cells at 20 pM with half-maximal effects at 40-50 pM, which is compatible with circulating αKlotho levels. Addition of recombinant αKlotho activated an antioxidant response element reporter and increased the levels of target proteins of the nuclear factor erythroid-derived 2 related factor system. In summary, αKlotho deficiency in AKI contributes to acute lung injury by reducing endogenous antioxidative capacity and increasing oxidative damage in the lung. αKlotho replacement partially reversed these abnormalities and mitigated pulmonary complications in AKI.

Atrial fibrillation: In the light of new hypothesis

BackgroundAtrial fibrillation (AF) is the most common cardiac arrhythmia. Many studies have investigated the cause for the development of AF, however, the question remains unanswered. MethodsA comparison of hydrodynamics between AF and sinus rhythm was performed. ResultsI proposed the hypothesis that atrial fibrillation is a protective physiological mechanism, based on the termination of atrial mechanical systole. This reduces the pressure in the system of the pulmonary veins and alveolar capillaries in pathological situations, and thus reduces the likelihood for development of pulmonary congestion and edema. ConclusionsThe hypothesis is well correlated with the known facts and phenomenons associated with AF, and explains the causes of the onset of AF in different conditions and diseases.

Les enjeux du diagnostic de rejet humoral en transplantation pulmonaire

In lung transplantation, there is a increased recognition on the deleterious role of DSA for chronic dysfunction of pulmonary graft. In order to optimize the therapeutic stategies and to guide clinical trials, the standardized definition of humoral reject (HR) criteria in lung transplantation proves to be necessary. The deposit of C4d complement, confirming the activation of secondary complement in interaction between DSA and target cells, is a reliable biomarker of HR in renal and cardiac transplantations. However, with the same histopathological criteria from HR of kidney and heart, which is less robust when applying in lung transplantation. The sometime contradictory results of C4d are in part linked to variability between medical centers and in the interpretation of this marker. Although no definition of the criteria of HR had been established, ISHLT (International Society for Heart and Lung Transplantation) recommends a multidisciplinary approach to HR for lung transplantation, including the tripod diagnosis: 1) presence of clinical dysfunction, 2) presence of DSA and 3 ) presence of histopathological lesions of C4d with endothelial deposit in the alveolar capillaries.