ANNULATE LAMELLAE IN GASTRIC CARCINOMA

A 72-year-old male painter, who complained of his "lungs burning" for 2 weeks, died suddenly. Autopsy examination revealed severe coronary atherosclerosis with plaque rupture as the cause of death. Examination of the lungs revealed emphysema, interstitial fibrosis, and multinucleated giant cells with intra- and extracellular brown-black, crystalline, polarizable foreign material. Energy-dispersive X-ray microanalysis showed the material to contain titanium, aluminum, silicon, and iron. An increased incidence of respiratory disease has been reported in professional painters. Titanium is widely used as a pigment in the manufacturing of commercial paints. Cases of pneumoconiosis and alveolar proteinosis have been described in painters in which analysis of lung tissue revealed increased levels of titanium. This case is presented as an example of a rarely reported phenomenon, which may have clinical implications for evaluation and management of lung disease in painters.     

Horseshoe lung: report on a new variant--"inverted" horseshoe lung--with embryological reflections on the formal pathogenesis of horseshoe lungs.

The term "horseshoe lung" is used to describe a rare congenital anomaly of the lungs that is characterized by the presence of a midline isthmus of pulmonary parenchyma connecting the posterobasal regions of the right and left lungs. Since the introduction of the term horseshoe lung in the 1960's, almost 40 cases have been reported in the literature. In all these cases, the right and left lungs were joined in their posterobasal regions, the situation resembling that found in horseshoe kidneys. Here we present a case of connection between the right and left lungs found during necropsy of a human fetus. In this case, a midline isthmus of pulmonary parenchyma covered by visceral pleura joined the apical regions of the right and left lungs behind the trachea and esophagus. This connection resulted in a "horseshoe"-shaped lung in which the "horseshoe" was turned by 180 degrees compared to classical cases of horseshoe lung. To the best of our knowledge, this is the first report on an "inverted" horseshoe lung. Embryological reflections on the formal pathogenesis of inverted and classical horseshoe lungs are presented.     

Donor lungs with pulmonary embolism evaluated with ex vivo lung perfusion

Acute pulmonary embolism (PE) compromises oxygenation and is typically considered a contraindication to lung donation for transplantation. We report the use of ex vivo lung perfusion (EVLP) to evaluate and possibly improve a pair of donor lungs with PE and poor oxygen exchange to a condition that might have been suitable for subsequent transplantation. A pair of donor lungs was procured for research after being declined for clinical use and placed on the EVLP circuit for 7 hours. Functional monitoring of the lungs revealed an increase in the partial pressure of oxygen to fraction of inspired oxygen ratio (P/F ratio) from 268 in situ to 458 after EVLP. While on the circuit, pulmonary vascular resistance decreased as dynamic compliance of the lungs increased, suggesting they might have been acceptable for transplantation.     

Infection-induced airway fibrosis in two rat strains with differential susceptibility.

Chronic infections play a significant role in the morbidity and mortality of patients with chronic airflow limitation. By stimulating airway inflammation, persistent infection has the potential to cause airway fibrosis. However, in patient this condition is most typically found in lungs damaged by other factors, such as smoking, abnormal secretions, or barotrauma. We report the characterization of Mycoplasma pulmonis infection-induced lung fibrosis in two immunocompetent rat strains with no preexisting lung disease. The fibrosis was predominantly in the airways, as demonstrated by the findings for infected animals of increased airway inflammation, airway fibrosis, and airway wall thickness, which correlated with the collagen content of the lungs. Also, the physiological alterations were the opposite of those found in interstitial fibrosis, with a positive correlation between lung compliance and collagen content. The airway fibrosis was noted earlier and to a greater extent in Lewis rats than in Fisher rats, and this result apparently was related to regulation of the inflammatory response. Airway wall thickness, airway inflammation, and airway fibrosis are commonly reported in tissue specimens from patients with chronic airway diseases and have been shown to correlate with airflow limitation in patients with chronic obstructive pulmonary disease. Thus, this model may be useful in furthering our understanding of the role of chronic infection and airway inflammation in airflow obstruction.     

Advances in artificial lungs

Artificial lungs have already been developed as complete artificial organs, and results of many investigations based on innovative concepts have been reported continuously. In open-heart surgery, artificial lungs are used for extracorporeal circulation to maintain gas exchange, and the commercial products currently available perform adequately, including providing for antithrombogenicity. However, patients after cardiopulmonary arrest or severe respiratory/circulatory failure have required long-term assist with extracorporeal membrane oxygenation (ECMO). The number of artificial lungs used for ECMO in those cases has shown significant growth in recent years. Therefore, it is expected that durability and antithrombogenicity will ensure the prolonged use of an artificial lung for several weeks or months. Furthermore, interests in research are shifting to use of oxygenators as a bridge to lung transplantation and an implantable artificial lung. This paper discusses recent advances in artificial lungs, focusing on the current state and on trends in research and development.     

Early neutrophil but not eosinophil or platelet recruitment to the lungs of allergic horses following antigen exposure

Previous studies have shown that bronchoalveolar lavage fluid from horses with allergic respiratory disease and showing clinical symptoms contains increased numbers of neutrophils. In some cases, the eosinophil count is also increased. In this study the time course of changes in lung function and the accumulation of radiolabelled leucocytes and platelets in the lungs of allergic and normal horses has been examined during a 7 hr allergen exposure. Antigen challenge had no effect on pleural pressure or the distribution of radiolabelled neutrophils, eosinophils or platelets in normal horses. In contrast, in 6/8 allergic horses, there was an increase in pleural pressure and neutrophil accumulation in the lungs, both of which were evident after 4-5 hr. However, during the 7 hr challenge period radiolabelled eosinophils were detected in the lungs of only 1/6 horses exhibiting an increase in pleural pressure and in 1/7 horses that failed to show a change in airway function despite a clinical history of allergic respiratory disease. Antigen challenge did not alter the distribution of radiolabelled platelets in the five allergic horses tested. These results demonstrate that increased pleural pressure is not accompanied by eosinophil or platelet accumulation in the lungs of horses with allergic respiratory disease following exposure to antigen. However, changes in airway function can be associated with neutrophil accumulation but can also take place in the absence of this cell recruitment. This raises the possibility that the presence of neutrophils in the lung is not a prerequisite for changes in lung function.     

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.Emphysema is a major subset of chronic obstructive pulmonary disease (COPD) and is defined anatomically as the destruction of the distal lung parenchyma and enlargement of the air spaces. Pulmonary emphysema is one of the main causes of morbidity and death worldwide. The most studied factor in developing COPD has long been recognized to be cigarette smoking. However, only 10% to 20% of heavy smokers develop clinically significant COPD.^1,2 Importantly, recent studies indicate that complementary pathogenic mechanisms, such as proteolytic/antiproteolytic imbalance, oxidative stress, apoptosis, or altered innate immunity, are involved in the development and progression of alveolar destruction.^3–6Cathepsins have been implicated in mediating alveolar destruction via their proteolytic activity. Cathepsins are intracellular hydrolases and include serine proteases (cathepsins A and G), aspartic proteases (cathepsins D and E), and cysteine cathepsins (cathepsins B, C, F, H, K, L, O, S, V, X, and W). Cathepsin E (Cat E), a nonlysosomal intracellular aspartic protease, is homologous to aspartic protease cathepsin D, a major proteolytic activity in the lysosomal component.⁷ Recent studies have reported that Cat E plays an important role in antigen processing via the major histocompatibility complex class II pathway, host defense against cancer cells and invading microorganisms, gastric differentiation, and development of signet-ring cell carcinoma.^8–12 However, Cat E has not been linked to lung disease.Human lung sections from persons with COPD indicated increased expression of Cat E protein in the lung epithelial cells. To investigate if increased expression of lung epithelial Cat E could lead to emphysema, we generated lung-targeted constitutive and inducible Cat E transgenic (Tg) mice. Our data indicated that inducible Cat E Tg mice developed emphysema-like lung changes as early as 1 week. We noted robust caspase 3 activation, and, when mice were administered a caspase inhibitor, emphysema was prevented. To our surprise, we did not find changes in caspases usually associated with caspase 3 activation, such as caspases 8 and 9, in Cat E Tg mice. Instead, we found significant induction of a mitochondrial fission protein, dynamin-related protein 1 (Drp1). When we inhibited Drp1 in Cat E Tg mice with Mdivi-1, a small molecule Drp1 inhibitor, we completely abolished the development of emphysema. Collectively, our data indicate that increased Cat E is a clinically relevant finding in human COPD and invoke a novel role for Cat E in mitochondrial fission-induced emphysema.     

Clinico-pathological Analysis of the Lungs from Patients with Lung Transplantation in a Single Institute in Korea

Recently, the numbers of lung transplantation (LT) has been increased in Korea. However, post-LT outcome has not been successful in all patients, which may be partially affected by the primary lung disease. Therefore comprehensive understanding in original pathological diagnosis of patients with LT would be needed for achieving better clinical outcome. To address this issue, we performed clinico-pathological analysis of the explanted lungs from 29 patients who underwent LT over a 9-yr period in Seoul National University Hospital. Among them, 26 patients received single (1/26) or double (25/26) LT, while heart-lung transplantation was performed in 3 patients. The final clinico-pathological diagnoses were idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) (n = 6), acute interstitial pneumonia (AIP)/diffuse alveolar damage (DAD) (n = 4), AIP/non-specific interstitial pneumonia with DAD (n = 1), collagen vascular disease-related interstitial lung disease (CVD-ILD)/DAD (n = 3), CVD-ILD/UIP (n = 1), lymphangioleiomyomatosis (n = 1), bronchiectasis (n = 4), pulmonary arterial hypertension (n = 2), tuberculosis (n = 1), bronchiolitis obliterans (BO) (n = 1), and lung cancer (n = 1). Moreover, 4 patients who had chemotherapy and hematopoietic stem cell transplantation due to hematologic malignancy showed unclassifiable interstitial pneumonia with extensive fibrosis in the lungs. Our study demonstrates that pathology of the explanted lungs from Korean patients with LT is different from that of other countries except for interstitial lung disease and bronchiectasis, which may be helpful for optimization of selecting LT candidates for Korean patients.

Graphical Abstract

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The surface properties of the lung in rats with alveolar lipo-proteinosis.

The physical behaviour of the intact lungs and of lung extracts from rats affected by alveolar lipo-proteinsosis as a consequence of silica inhalation, was studied by means of pressure volume relations and surface tension area loops. Air inflation of diseased lungs occurred at a lower pressure and collapse was less on deflation than in control specimens, although there appeared to be little change in elastic forces. When saline was used dusted rat lungs showed at higher lung volumes a peculiar hysteresis effect which is attributable to consolidation of alveoli by the lipid material. Extracts from affected lungs showed differences from controls in respect of maximum and minimum surface tensions and stability index but all the values fell within the accepted limits of normal. However, with extracts from pathological lungs the area of the hysteresis loop increased, the shape of the surface tension area curve was abnormal and the percentage compression required to reduce the surface tension to 120 muN/cm fell. Extracts from diseased lungs depressed the maximum surface tension of normal lung extracts and increased the hysteresis area but had little effect on the minimum tension, the stability index or the % compression to achieve 120 muN/cm. The response was thus mainly that of an extract from a dusted rat. The surface activity of phospholipids may be affected by neutral lipid, cholesterol and the products of cell breakdown, all of which occur in the alveolar material. The occurrence within the same lung of compunds which reduce surface tension and others which modify the same lung of compounds which reduce surface tension and others which modify this property suggests that their relative concentrations may determine the overall effectiveness of the lung lining.     

Ultrastructural evaluation of lung maturation in a sheep model of diaphragmatic hernia and tracheal occlusion

In fetuses with diaphragmatic hernia (DH) lung development is impaired, and pulmonary hypoplasia is one of the main factors responsible for the poor outcome of the disease. A possible treatment consists of occluding trachea during lung development to retain pulmonary fluid and to force the lung to expand. Although it appeared promising at first, this technique has recently been reported to decrease type II cell number and to induce surfactant deficiency. The aim of this study was to investigate lung maturation further through ultrastructural examination in a fetal lamb model of DH created at 85 d, followed or not by endoscopic balloon tracheal occlusion (TO) at 120 d of gestation. The proportion of alveolar epithelial type I and type II cells was altered by both treatments: the type I/type II cell ratio, which was about 2 in control lungs, was decreased 4.5-fold in DH lungs but was increased 4.5-fold in DH+TO lungs. The proportion of undifferentiated cells was increased in DH lungs. Indeterminate cells sharing features of type II and type I cells that were not observed in controls were seldom seen in DH lungs and were numerous in DH+TO lungs. The number of lamellar bodies per type II cell was decreased in both DH and DH+TO groups. In DH lungs, wall structure presented an immature appearance, with cellular connective tissue and poor secondary septation of saccules. In DH+TO lungs, primary septa appeared more mature, with reduced connective tissue, but secondary septa were still buds, although elastin was present at their tips. A single capillary layer was found in all three groups (control, DH, and DH+TO) with no sign of septal capillary pairing. This first investigation in DH and DH+TO lungs through transmission electron microscopy thus enabled us to show that compression and forced expansion of the lung are both responsible for alterations in type II cell differentiation and septal development.     

Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of the symptoms, therapeutic strategies have been ineffective. High mobility group box 1 (HMGB1), which was identified originally as a DNA binding protein, has been proposed as a mediator of acute lung injury. In addition to its anti‐coagulant activity, recombinant thrombomodulin (rTM) possesses an ability to suppress the inflammatory response through neutralizing HMGB1. T regulatory (T_reg) cells in the lungs are reported to modify innate immune responses during resolution of acute lung injury. In the present study, we investigated the therapeutic effect of rTM, and the contribution of T_reg cells to this effect, in a mouse model of severe ARDS. C57BL/6 mice received sequential intratracheal administration of α‐galactosylceramide (α‐GalCer) and lipopolysaccharide (LPS), which resulted in the development of severe ARDS. HMGB1 levels in the lungs increased to a higher level in ARDS mice compared to those in mice treated with LPS alone. HMGB1 was expressed in the infiltrating neutrophils and macrophages in lungs. T_reg cells were reduced significantly in the lungs of ARDS mice compared to those in mice treated with LPS alone. rTM administration prolonged the survival time and ameliorated the development of ARDS, which was associated with increased T_reg cells and synthesis of interleukin (IL)‐10 and transforming growth factor (TGF)‐β in the lungs. These results suggest that HMGB1 is involved in the development of severe ARDS and rTM shows therapeutic effects through promoting the accumulation of T_reg cells at the inflammatory sites.     

A computational evaluation of the effect of intramedullary nail material properties on the stabilization of simulated femoral shaft fractures

Titanium flexible intramedullary nails have become far more prevalent for stabilization of pediatric femur fractures in recent years. While steel may be expected to have superior fracture stability due to its higher elastic modulus; titanium alloy has experimentally demonstrated improved biomechanical stability, as measured by gap closure and nail slippage. The purpose of this study was to verify these observations computationally, and thus, explain why titanium alloy may be better suited for surgical fixation of fractured femurs. A finite element model of a femur with complete mid-diaphyseal fracture and having two 3.5 mm nails in a retrograde "C" pattern was created. Static analyses were run in which the nail material properties were titanium alloy or stainless steel, respectively. Gap closure for the stainless steel nails was 1.03 mm; while the titanium alloy nails had 0.69 mm of closure. Titanium alloy nails slipped slightly less at each loading increment than stainless steel nails. The titanium alloy nails distributed stress more evenly along the nail axis, resulting in lower peak magnitudes. These results agree with previously published clinical and biomechanical studies that reported increased gap closure and nail slippage with stainless steel nails. The increased deformation of the titanium alloy nail likely increases the contact area with the intramedullary canal wall, thus, increasing stability. Additionally, stainless steel nails had higher curve apex von Mises stresses, potentially inducing a stress-shielding effect which could hamper remodeling and consequently increase risk of re-fracture.     

Pulmonary pathology in patients associated with scrub typhus

AIMS: Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi. Severe cases resulting in mortality from this disease have rarely been reported. We present two scrub typhus cases (a man and a girl) who died of acute respiratory distress syndrome (ARDS). METHODS: Autopsies were performed. Histopathological and immunohistochemical stains were employed using specific antibody for O. tsutsugamushi and inducible nitric oxide synthase (iNOS). RESULTS: These subjects developed respiratory distress shortly after admission, and expired following respiratory failure. At autopsy, generalised lymphadenopathy was observed. The lung weight was about two-fold the normal value. Gross inspection revealed oedematous and haemorrhagic lungs. Microscopic examination revealed diffuse alveolar damage with hyaline membrane formation and interstitial pneumonitis with infiltration of inflammatory cells. Immunohistochemical stain showed O. tsutsugamushi antigen depositions in the endothelial cells. We also demonstrated iNOS in the alveolar macrophages and lung tissue debris in both cases. CONCLUSION: Scrub typhus is usually a mild infectious disease. Our cases present the most dramatic example of sudden death due to ARDS in a short period of time. The clinical investigation and analysis suggest direct endothelial cell invasion of the organism and marked iNOS expression may be involved in the pathogenesis of ARDS associated with scrub typhus.     

The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury

Inflammatory stimuli, such as a microbes or lipopolysaccharides, induce a rapid release of neutrophils from the bone marrow and promote neutrophil migration into inflamed sites to promote host defense. However, an excess accumulation and retention of neutrophils in inflamed tissue can cause severe tissue injuries in the later stages of inflammation. Recent studies have reported that both CXCL12 levels in injured lungs and its receptor, CXCR4, on accumulated neutrophils in injured lungs, increased; furthermore, these studies showed that the CXCL12/CXCR4 signaling pathway participated in neutrophil accumulation in the later stages of lipopolysaccharide (LPS)-induced lung injury. However, the mechanisms underlying this increase in surface CXCR4 expression in neutrophils remain unclear. In this study, we found that surface CXCR4 expression increased in extravascular, but not intravascular, neutrophils in the lungs of LPS-induced lung injury model mice. Furthermore, ex vivo studies revealed that CXCL12 acted not only as a chemoattractant, but also as a suppressor of cell death for the lung neutrophils expressing CXCR4. Sulfatide, one of the native ligands for L-selectin, induced the increase of surface CXCR4 expression on isolated circulating neutrophils, suggesting that the activation of L-selectin may be involved in the increase in surface CXCR4. Our findings show that surface CXCR4 levels on neutrophils increase after extravasation into injured lungs, possibly through the activation of L-selectin. The CXCL12/CXCR4 signaling pathway plays an important role in the modulation of neutrophil activity during acute lung injury, not only by promoting chemotaxis but also by suppressing cell death.     

Quantitative immunohistologic assessment of lymphocyte populations in the pulmonary inflammatory response to intratracheal silica.

Immunogold-silver staining was used to identify T lymphocytes, T lymphocyte subsets, and B lymphocytes in lung tissue from mice injected intratracheally with silica, titanium dioxide, or saline alone. Morphometric quantitation revealed a marked influx of T lymphocytes in the silica-treated animals during the first 3 weeks after injection. The relative numerical density of these cells remained elevated when compared with saline-treated controls throughout the 12 weeks of the experiment. Cells expressing the CD4 and CD8 antigens were both increased in number, with the former accounting for approximately two-thirds of the T lymphocytes. An increased number of B lymphocytes was also apparent from 6 weeks after treatment with silica. The T lymphocyte response preceded the development of significant pulmonary fibrosis by several weeks. No lymphocyte response was observed in the lungs of mice injected with nonfibrogenic titanium dioxide. These observations are consistent with the hypothesis that lymphokines secreted by T lymphocytes play a role in the pathogenesis of silicotic inflammatory lesions and their progression to fibrosis.     

Array-CGH and quantitative PCR genetic analysis in a case with bilateral hypoplasia of pulmonary arteries and lungs and simultaneous unilateral renal agenesis

We describe the clinical course and have characterised anatomically and genetically a unique case of a newborn with bilateral hypoplasia of pulmonary arteries, consecutive extremely hypoplastic lung tissue and associated unilateral renal agenesis. Intrauterine oxygenation by the placenta seemed to have allowed normotrophic body maturity but immediately after delivery, in the third trimester, progressive hypoxemia developed and the newborn succumbed to acute respiratory failure. Genetic analysis by array-based comparative genomic hybridisation and quantitative PCR revealed duplication of 1p21, which, however, might not be the disease causing aberration. This case might represent an extreme form of previously reported, rare cases with simultaneous dysorganogenesis of lungs and kidneys.     

Increased elastin production in experimental granulomatous lung disease.

In the normal, healthy lung, elastin production is restricted to periods of development and growth. However, elastin expression in the adult lung has been observed in some forms of pulmonary injury, including pulmonary fibrosis. Here, we report that elastin production is significantly increased within precise interstitial compartments of the lung in an experimental model of granulomatous lung disease. An increase in the number and volume of elastic fibers within the alveolar walls was apparent on histological examination of Verhoeff-van Gieson-stained sections of silicotic rat lungs. Quantitation of mature elastin cross-links indicated that silicosis was accompanied by a 17-fold increase in lung elastin content when compared with values from saline-treated controls. In situ hybridization for tropoelastin mRNA revealed that elastin production was absent from granulomatous lesions yet was prominent at nonfibrotic alveolar septal tips, where a high density of elastic fibers is seen in the normal lung. Immunohistochemistry indicated tropoelastin was being expressed by alpha-smooth muscle actin-containing cells. Transforming growth factor-beta was immunolocalized to granulomatous regions of the silicotic lung but was absent from regions showing increased tropoelastin expression. These data indicate that the reinitiation of tropoelastin gene expression is associated with granulomatous lung disease, and this expression leads to the aberrant accumulation of mature elastin in the lung.