肺的氧化应激及抗氧化剂的干预作用

肺的氧化应激是体内氧化抗氧化平衡失调所致，局部可产生大量的反应性氧化物和反应性氮化物，它们有多种生理作用如调节基因表达和细胞凋亡等，但过度产生时会直接损伤组织并诱发炎症级联反应。抗氧化剂可以通过维持氧化／抗氧化平衡减少肺脏损伤。氧化／抗氧化失衡是许多肺疾病如哮喘、慢性阻塞性肺气肿、急性呼吸窘迫综合征、特发性肺纤维化以及囊性纤维化的病理基础，本文就过度氧化和氧化应激在肺部疾病中作用以及抗氧化剂的干预作一综述。     

Bronchospasm disclosing pulmonary embolism

We report the case of an 82-year old male patient without history of chronic obstructive lung disease in whom a sudden respiratory distress syndrome with sibilant rales in both lungs revealed a moderately severe pulmonary embolism, later confirmed by angiography. Bronchospasm occurring in the acute phase of pulmonary embolism may be expressed as acute asthma refractory to bronchodilators. This bronchoconstriction, seldom detectable clinically, seems to be related to regional alveolar hypocapnia in the territories embolized and to platelet-produced mediators, through a vagus nerve-mediated reflex. It must not hide pulmonary embolism, particularly in a suggestive context and when bronchodilators are ineffective.     

St. George's Hospital questionnaire (St. George's Respiratory Questionnaire) as an instrument for quality of life assessment in respiratory tract diseases

St. George's Respiratory Questionnaire (SGRQ) is one of the main measures of the quality of life in patients with pulmonary diseases. We review the literature concentrating the use of SGRQ in patients with asthma, chronic obstructive pulmonary disease, bronchectases, interstitial lung disease and in adult respiratory distress syndrome (ARSD).     

Effect of surfactant on ventilation-induced mediator release in isolated perfused mouse lungs

The human acute respiratory distress syndrome (ARDS) is a severe pulmonary complication with high mortality rates. To support their vital functions, patients suffering from ARDS are mechanically ventilated. Recently it was shown that low tidal volume ventilation reduces mortality and pro-inflammatory mediator release in these patients, suggesting biotrauma as a side effect of mechanical ventilation. Because the application of exogenous surfactant has been proposed as a treatment for ARDS, we investigated the effect of surfactant on ventilation-induced release of tumor necrosis factor (TNF), interleukin-6 (IL-6) and 6-keto-PGF(1 alpha) (the stable metabolite of prostacyclin) in isolated perfused mouse lungs ventilated with high end-inspiratory pressures. Instillation of 100mg/kg surfactant into the lungs was well tolerated and improved tidal volume, pulmonary compliance and alveolar expansion. Exogenous surfactant increased the ventilation-induced liberation of TNF and IL-6 into the perfusate, but had no effect on the release of 6-keto-PGF(1 alpha). The surfactant preparation used reduced baseline TNF production by murine alveolar macrophages, indicating that the exaggeration of ventilation-induced TNF release cannot be explained by a direct effect of surfactant on these cells. We hypothesize that ventilation-induced mediator release is explained by stretching of lung cells, which is reinforced by surfactant. The findings that in this model of ventilation-induced lung injury exogenous surfactant at the same time improved lung functions and enhanced mediator release suggest that surfactant treatment may prevent barotrauma and augment biotrauma.     

Cis-acting sequences from a human surfactant protein gene confer pulmonary-specific gene expression in transgenic mice.

Pulmonary surfactant is produced in late gestation by developing type II epithelial cells lining the alveolar epithelium of the lung. Lack of surfactant at birth is associated with respiratory distress syndrome in premature infants. Surfactant protein C (SP-C) is a highly hydrophobic peptide isolated from pulmonary tissue that enhances the biophysical activity of surfactant phospholipids. Like surfactant phospholipid, SP-C is produced by epithelial cells in the distal respiratory epithelium, and its expression increases during the latter part of gestation. A chimeric gene containing 3.6 kilobases of the promoter and 5'-flanking sequences of the human SP-C gene was used to express diphtheria toxin A. The SP-C-diphtheria toxin A fusion gene was injected into fertilized mouse eggs to produce transgenic mice. Affected mice developed respiratory failure in the immediate postnatal period. Morphologic analysis of lungs from affected pups showed variable but severe cellular injury confined to pulmonary tissues. Ultrastructural changes consistent with cell death and injury were prominent in the distal respiratory epithelium. Proximal components of the tracheobronchial tree were not severely affected. Transgenic animals were of normal size at birth, and structural abnormalities were not detected in nonpulmonary tissues. Lung-specific diphtheria toxin A expression controlled by the human SP-C gene injured type II epithelial cells and caused extensive necrosis of the distal respiratory epithelium. The absence of type I epithelial cells in the most severely affected transgenic animals supports the concept that developing type II cells serve as precursors to type I epithelial cells.     

Extracellular vesicles: Their emerging roles in the pathogenesis of respiratory diseases

Alveoli are the basic structure of the lungs, consisting of various types of parenchymal and bone marrow-derived cells including alveolar macrophages. These various types of cells have several important functions; thus, communication between these cells plays an important role in homeostasis as well as in the pathophysiology of diseases in the lungs. For a better understanding of the pathophysiology of lung diseases, researchers have isolated each type of lung cell to investigate the changes in their gene expressions, including their humoral factor or adhesion molecules, to reveal the intercellular communication among these cells. In particular, investigations during the past decade have focused on extracellular vesicles, which are lipid bilayer delimited vesicles released from a cell that can move among various cells and transfer substances, including microRNAs, mRNAs and proteins, thus, functioning as intercellular messengers. Extracellular vesicles can be classified into three general groups: apoptotic bodies, exosomes, and microparticles. Extracellular vesicles, especially exosomes and microparticles, are attracting increasing attention from pulmonologists as tools for understanding pathogenesis and disease diagnosis. Here, we review studies, including our own, on exosomes and microparticles and their roles in both lung homeostasis and the pathogenesis of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive lung diseases, and acute respiratory distress syndrome. This review also addresses the roles of extracellular vesicles in COVID-19, the current global public health crisis.     

颗粒蛋白前体在呼吸系统疾病的研究进展

颗粒蛋白前体(PGRN)是多功能的生长因子,在正常组织的发生、增生、再生、宿主防御的动态调节中起重要作用.诸多研究表明PGRN参与传染病、伤口愈合、肿瘤发生、神经增殖和退化性疾病.目前研究发现PGRN在炎性疾病中发挥重要作用,此外,PGRN在COPD、ARDS、非小细胞肺癌、间质性肺病中也有研究,本文就PGRN在肺部疾病中的研究进展进行综述.     

Isolated type II cells from fetal lung as model in studies on the synthesis and secretion of pulmonary surfactant

The alveoli of the lung are lined by a surfactant layer which prevents alveolar collapse. Fetal surfactant formation is turned on at the end of gestation. A deficiency of this pulmonary surfactant due to immaturity of the lungs causes the respiratory distress syndrome of the newborn. The surfactant is synthesized in the alveolar type II epithelial cells. Most studies concerning the synthesis of surfactant have been carried out with preparations of whole lung. Because of the cellular heterogeneity of the lung these biochemical observations cannot be attributed directly to the type II cells. Recently methods have become available for the isolation and culture of type II cells from fetal lung. This article gives a review of these methods and of the biochemical studies carried out with the isolated fetal type II cells.     

Altered stability of pulmonary surfactant in SP-C-deficient mice

The surfactant protein C (SP-C) gene encodes an extremely hydrophobic, 4-kDa peptide produced by alveolar epithelial cells in the lung. To discern the role of SP-C in lung function, SP-C-deficient (-/-) mice were produced. The SP-C (-/-) mice were viable at birth and grew normally to adulthood without apparent pulmonary abnormalities. SP-C mRNA was not detected in the lungs of SP-C (-/-) mice, nor was mature SP-C protein detected by Western blot of alveolar lavage from SP-C (-/-) mice. The levels of the other surfactant proteins (A, B, D) in alveolar lavage were comparable to those in wild-type mice. Surfactant pool sizes, surfactant synthesis, and lung morphology were similar in SP-C (-/-) and SP-C (+/+) mice. Lamellar bodies were present in SP-C (-/-) type II cells, and tubular myelin was present in the alveolar lumen. Lung mechanics studies demonstrated abnormalities in lung hysteresivity (a term used to reflect the mechanical coupling between energy dissipative forces and tissue-elastic properties) at low, positive-end, expiratory pressures. The stability of captive bubbles with surfactant from the SP-C (-/-) mice was decreased significantly, indicating that SP-C plays a role in the stabilization of surfactant at low lung volumes, a condition that may accompany respiratory distress syndrome in infants and adults.     

Foxa2 is required for transition to air breathing at birth

Toward the end of gestation in mammals, the fetal lung undergoes a process of differentiation that is required for transition to air breathing at birth. Respiratory epithelial cells synthesize the surfactant proteins and lipids that together form the pulmonary surfactant complex necessary for lung function. Failure of this process causes respiratory distress syndrome, a leading cause of perinatal death and morbidity in newborn infants. Here we demonstrate that expression of the forkhead gene Foxa2 in respiratory epithelial cells of the peripheral lung controls pulmonary maturation at birth. Newborn mice lacking Foxa2 expression in the lung develop severe pulmonary disease on the first day of life, with all of the morphological, molecular, and biochemical features of respiratory distress syndrome in preterm infants, including atelectasis, hyaline membranes, and the lack of pulmonary surfactant lipids and proteins. RNA microarray analysis at embryonic day 18.5 demonstrated that Foxa2-regulated expression of a group of genes mediating surfactant protein and lipid synthesis, host defense, and antioxidant production. Foxa2 regulates a complex pulmonary program of epithelial cell maturation required for transition to air breathing at birth.     

Lung albumin recovery in surfactant-treated preterm ventilated lambs.

Preterm ventilated animals and infants with respiratory distress syndrome (RDS) develop proteinaceous alveolar edema. To study the effect of postnatal age on intravascular radiolabeled albumin accumulation into lungs, preterm lambs at 132 days gestational age were ventilated after treatment with sheep surfactant or cow surfactant extract for periods as long as 24 h. Lambs not treated with surfactant were studied for only 5 h because of severe respiratory failure. All lambs were given radiolabeled albumin by intravascular injection 1 h before they were killed, and the net recovery of the labeled albumin was measured in the lung tissue and air space as quantified by alveolar lavage. Net 1-h radiolabeled albumin recoveries in the lungs decreased from 5 to 6% soon after birth to 0.9% at 24 h in the surfactant-treated groups (p less than 0.01). At 3 h there was less labeled albumin recovery by alveolar lavages in lambs treated with sheep surfactant than in control lambs and lambs treated with cow surfactant extract (p less than 0.05). Protein in alveolar washes from lambs treated with cow surfactant extract exceeded that in lambs treated with sheep surfactant at 3 h (p less than 0.05), but protein recoveries had decreased to similar values by 24 h, indicating a net clearance of air-space protein. These studies demonstrate a sixfold decrease in net albumin accumulation from birth to 24 h of age despite continued ventilation and oxygen exposure of the premature lamb lungs.     

The future of surfactant therapy during ALI/ARDS

The importance of pulmonary surfactant in maintaining normal lung function, and the observations that alterations in endogenous surfactant contribute to the lung dysfunction associated with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), provide a rationale for administering exogenous surfactant in this setting. The results of clinical trials have been variable, however, in part due to the various surfactant preparations used, the different delivery and dosing methods employed, and the types of patients targeted for this therapy. Based on the insight gained from these studies, ongoing trials have modified these factors to optimize outcome, including one trial that is focusing on patients with direct lung insults such as pneumonia and aspiration. The future of surfactant therapy may well take advantage of the recently described host defense functions of this material. Based on extensive in vitro data as well as in vivo animal studies demonstrating the anti-inflammatory and antibacterial functions of various surfactant components, administration of surfactant earlier in the course of the disease, when lung inflammation is present but before severe lung dysfunction occurs, may prove to be optimal. This review discusses both the biophysical and host defense functions of surfactant in the context of novel therapeutic approaches for patients with ALI/ARDS.     

可溶性人基质裂解素2在肺部炎症性疾病的作用研究进展

可溶性人基质裂解素2 (soluble Suppression of tumorigenicity 2,sST2)是人基质裂解素2 (ST2)亚型之一,其可作为IL-33的受体,选择性表达于Th2细胞,在免疫反应和炎症疾病中发挥重要作用.近年研究发现IL-33与sST2结合,在肺部炎症性疾病中发挥重要作用,如社区获得性肺炎、慢性支气管炎、COPD、哮喘和ARDS.本文对sST2在肺部炎症性疾病中的作用研究进展作一综述.     

Decreased VEGF concentration in lung tissue and vascular injury during ARDS.

Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Decreased production of vascular endothelial growth factor (VEGF) in ARDS may favour vascular lesions, since VEGF promotes endothelial survival by inhibiting apoptosis. This study sought to document low VEGF levels in lung tissue from ARDS patients, to determine whether the cause was injury to alveolar type II cells (the main pulmonary source of VEGF) and to evaluate the vascular consequences. Lung specimens were obtained by open biopsy or autopsy from 29 patients with severe ARDS (two survivors) and five controls. As compared with controls, homogenates of lung tissue from ARDS patients contained less VEGF (median (interquartile range) ARDS 8.2 (4.7-12.2) versus controls 28.4 (9.9-47.1) ng x g(-1) protein). Increased immunostaining with surfactant protein B was seen in ARDS lungs. Extensive cellular apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining), including endothelial and alveolar type II cells, was demonstrated, and vascular bed density (CD31 immunostaining) decreased in ARDS lungs as compared with controls. VEGF levels were negatively correlated to apoptotic endothelial cell counts. In conclusion, decreased vascular endothelial growth factor levels in lung tissue may participate in the decrease in lung perfusion in acute respiratory distress syndrome.     

Randomized trial comparing two natural surfactants (Survanta vs. bLES) for treatment of neonatal respiratory distress syndrome

Exogenous surfactants have been used as an effective treatment of neonatal respiratory distress syndrome (RDS). Different preparations of surfactant carry different biophysical and clinical properties. To study the response pattern and treatment outcome of two natural surfactants (bLES and Survanta) for the treatment of RDS, we conducted a randomized clinical trial at the neonatal unit of a university teaching hospital. Premature babies with birth weight between 500-1,800 g who developed RDS requiring mechanical ventilation with an oxygen requirement of more than 30% within 6 hr of life were randomized into two treatment groups. Oxygenation indices (OIs) within 12 hr of treatment were compared as primary outcomes, while neonatal complications were analyzed as secondary outcomes of the study. Sixty babies were recruited, with 29 in the bLES and 31 in the Survanta treatment group. Both groups had significant and sustained improvements in OI after surfactant replacement therapy (SRT), while the bLES group was associated with a significantly lower OI throughout the initial 12 hr after treatment compared with the Survanta group. There was no difference in secondary outcomes including mortality, ventilator days, and occurrence of chronic lung disease. We conclude that infants with RDS respond favorably to both types of surfactant replacement, and that bLES achieved a faster clinical response in terms of improvement in OI than Survanta.     

Comparative trial of artificial and natural surfactants in the treatment of respiratory distress syndrome of prematurity: experiences in a developing country.

We conducted a randomized clinical trial to compare the effects of a synthetic (Exosurf) and natural (Survanta) surfactant in infants with neonatal respiratory distress syndrome. Eighty-nine patients were randomly allocated to receive one of the two surfactants. Primary outcome variables were the acute and long-term effects of the surfactant preparations, i.e., ventilatory requirements at 24 h of age as judged by the oxygenation index (OI), and the combined incidence of chronic lung disease or death at 28 days. The OIs in the Exosurf and Survanta groups at 24 h were the same (10.1 and 7, respectively; P > 0.05). The magnitude and rapidity of response, however, were greater for Survanta than for Exosurf. When arterial/alveolar oxygen tension ratios (a/A) were compared, the Exosurf group had a significantly worse a/A ratio at 24 h than the Survanta group (0.21 Exosurf vs. 0.37 Survanta; P < 0.05). The long-term outcome as judged by the combined incidence of death or chronic lung disease was not different in the two groups (18.6% Exosurf vs. 15.2% Survanta; P > 0.05). When the complications of prematurity were compared, there were no statistically significant differences between the two groups. We conclude that both preparations are reasonable choices for the treatment of respiratory distress syndrome of prematurity.     

Smoking-related interstitial lung diseases

Interstitial lung diseases (ILDs) encompass diverse clinicopathological disease entities ranging from idiopathic interstitial pneumonia (IIP) to interstitial pneumonia accompanied by collagen vascular diseases and diseases related to smoking, drug reactions, occupational environments, infections, and malignancies. Our focus is on the smoking-related interstitial lung diseases. Specifically, we focus on reports suggesting that chronic smoking is deeply involved in the disease pathogenesis and on reports suggesting that chronic smoking may influence the clinical course in terms of either disease severity or progression. Pulmonary Langerhans' cell granulomatosis (PLCG), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis with interstitial lung diseases (RB-ILD), interstitial pneumonia associated with rheumatoid arthritis, acute respiratory distress syndrome (ARDS), and idiopathic pulmonary fibrosis (IPF) are covered.     

无创通气治疗技术的临床应用研究进展

无创通气(noninvasive ventilation,NIV)具有使用方便、并发症少等优点,临床应用日趋广泛.NIV不仅可用于治疗慢性阻塞性肺疾病、支气管哮喘、急性肺损伤和急性呼吸窘迫综合征、心源性肺水肿等引起的呼吸衰竭,还可为外科手术和拒绝插管的有创通气患者提供通气支持以及协助有创通气患者早期拔管脱机等.本文综述了近年来NIV的临床应用进展.     

Pulmonary vascular endothelial growth factor-C in development and lung injury in preterm infants

RATIONALE: In mice, vascular endothelial growth factor-C (VEGF-C) plays an important role in development of the lymphatic system and in pathogenesis of pulmonary inflammation. Its role in development of the lymphatic system in human lung and in lung injury in newborns remains unclear. OBJECTIVES: We studied the role of VEGF-C in developing human lung, and in acute and chronic lung injury in preterm infants. METHODS: Included in the immunohistochemistry study were 10 fetuses, 15 control neonates without primary lung disease, 15 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia. Tracheal aspirate fluid samples of intubated very-low-birth-weight infants during Postnatal Weeks 1-5 were analyzed with ELISA. RESULTS: Bronchiolar staining for VEGF-C was observed in all 48 samples. Alveolar epithelial staining was seen in most fetuses (8/10). In addition, staining was observed in alveolar macrophages in bronchopulmonary dysplasia (4/8), and late respiratory distress syndrome (2/7). VEGF receptor-3 (VEGFR-3) staining was observed in lymphatic endothelium adjacent to vascular endothelium. VEGF-C was expressed consistently in tracheal aspirate fluid, being highest during the first 2 postnatal days. Antenatal administration of glucocorticoids was associated with higher VEGF-C in tracheal aspirate fluid. CONCLUSIONS: The pattern of pulmonary VEGF-C and VEGFR-3 protein expression and consistent VEGF-C protein appearance in tracheal aspirate fluid in human preterm infants indicate a role for VEGF-C in the physiologic development of the lymphatic system of the lung.     

Chronic lung injury in preterm lambs. Disordered respiratory tract development

The cause of chronic lung disease of early infancy, often called bronchopulmonary dysplasia (BPD), remains unclear, partly because large-animal models that reliably reproduce BPD have not been available. We developed a model of BPD in lambs that are delivered prematurely and ventilated for 3 to 4 wk after birth to determine whether the histopathology of chronic lung injury in premature lambs mimics that which occurs in preterm infants who die with BPD, and to compare two ventilation strategies to test the hypothesis that differences in tidal volume (VT) influence histopathologic outcome. The two ventilation strategies were slow, deep ventilation (20 breaths/min, 15 +/- 2 ml/kg body weight VT; n = 5) or rapid, shallow ventilation (60 breaths/min, 6 +/- 1 ml/kg body weight VT; n = 5). Lambs were delivered at 125 +/- 4 d gestation (term = 147 d), treated with surfactant, and mechanically ventilated with sufficient supplemental oxygen to maintain normal arterial oxygenation (60 to 90 mm Hg). Quantitative histologic analysis revealed lung structural abnormalities for both groups of experimental lambs compared with lungs of control term lambs that were < 1 d old (matched for developmental age; n = 5) or 3 to 4 wk old (matched for postnatal age; n = 5). Compared with control lambs, chronically ventilated preterm lambs had pulmonary histopathology characterized by nonuniform inflation patterns, impaired alveolar formation, abnormal abundance of elastin, increased muscularization of terminal bronchioles, and inflammation and edema. Slow, deep ventilation was associated with less atelectasis, less alveolar formation, and more elastin when compared with rapid, shallow ventilation. We conclude that prolonged mechanical ventilation of preterm lambs disrupts lung development and produces pulmonary histopathologic changes that are very similar to those that are seen in the lungs of preterm infants who die with BPD. This chronic lung disease is not prevented by surfactant replacement at birth, does not appear to require arterial hyperoxia, and is influenced by VT.