Genetic polymorphism in matrix metalloproteinase-9 and transforming growth factor-β1 and susceptibility to combined pulmonary fibrosis and emphysema in a Chinese population

In this study, we aimed to explore the association of genetic polymorphism in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1) and the susceptibility to combined pulmonary fibrosis and emphysema (CPFE). We examined the polymorphisms of the MMP-9 C-1562T and TGF-β1 T869C in 38 CPFE patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis (IPF) patients. The frequencies of polymorphic genotypes in MMP-9 were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in emphysema group, and 100.0% CC in IPF group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and emphysema groups compared with IPF group (p < 0.05). The frequencies of polymorphic genotypes in TGF-β1 were 2.63% CC, 28.95% CT, 68.42% TT in CPFE group, 4.00% CC, 16.00% CT, 80.00% TT in emphysema group, and 5.88% CC, 41.18% CT, 52.94% TT in IPF group. Significant increases in the TT genotype and T allele frequencies were observed in emphysema group compared with IPF group (p < 0.05). Our study has showed that T allele in MMP-9 (C-1562T) and T allele in TGF-β1 (T869C) are risk factors of pulmonary emphysema. The T allele in MMP-9 (C-1562T) possibly predisposes patients with pulmonary fibrosis to develop emphysema.     

Diagnostic Values For Club Cell Secretory Protein (CC16) in Serum of Patients of Combined Pulmonary Fibrosis and Emphysema

Combined pulmonary fibrosis and emphysema (CPFE) is an under-recognized syndrome for which the diagnostic use of serum biomarkers is an attractive possibility. We hypothesized that CC16 and/or TGF-β1 or combinations with other biomarkers are useful for diagnosing CPFE. Patients with respiratory symptoms and a smoking history, with or without chronic obstructive pulmonary disease, were divided into the following three groups according to findings of high-resolution computed tomography of the chest: controls without either emphysema or fibrosis, patients with emphysema alone, and patients compatible with the diagnosis of CPFE. Serum concentrations of CC16, TGF-β1, SP-D, and KL-6 were measured in patients whose condition was stable for at least 3 months. To investigate changes in biomarkers of lung fibrosis in patients with a life-long smoking history, additional measurements were performed on the patients with idiopathic pulmonary fibrosis (IPF) of smoking history. The mean age of the first three groups was 68.0 years, whereas that of the IPF group was 71.8 years, and the groups contained 36, 115, 27, and 10 individuals, respectively. The serum concentration of CC16 in the four groups was 5.67 ± 0.42, 5.66 ± 0.35, 9.38 ± 1.04 and 22.15 ± 4.64 ng/ml, respectively, indicating that those patients with lung fibrosis had a significantly higher concentration. The combined use of CC16, SP-D, and KL-6 provided supportive diagnosis in conjunction with radiological imaging in diagnosis of CPFE. We conclude that a combination of biomarkers including CC16 could provide useful information to screen and predict the possible diagnosis of CPFE.     

Diaphragmatic Motion Studied by M-mode Ultrasonography in Combined Pulmonary Fibrosis and Emphysema

Background

The coexistence of emphysema and pulmonary fibrosis is known as combined pulmonary fibrosis and emphysema (CPFE). The aim of this study was to compare diaphragmatic motion measured by M-mode ultrasonography of patients with CPFE, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD).

Methods

Pulmonary function, high-resolution computed tomography (HRCT), and diaphragmatic motion were examined in patients with CPFE (n = 25), IPF (n = 18), and COPD (n = 60), and in healthy controls (n = 21). Diaphragmatic motions were measured on M-mode ultrasonographic images during quiet breathing and deep breathing.

Results

There were no significant differences in right or left diaphragmatic motion during quiet breathing among the four groups, whereas differences were significant in right and left motion during deep breathing. Diaphragmatic motion in CPFE patients was the lowest among the four groups. COPD patients, especially those with severe COPD, showed significantly lower diaphragmatic motion than IPF patients or healthy controls. There were no differences in diaphragmatic motion between IPF patients and healthy controls. Right diaphragmatic motions during deep breathing were negatively correlated with emphysema scores (r = ?0.606, p < 0.001), but were not correlated with fibrosis scores on HRCT.

Conclusions

Diaphragmatic weakness was found in CPFE patients. Emphysema but not fibrosis may be one cause of limited diaphragmatic motion in patients with CPFE. M-mode ultrasonographic evaluation of diaphragmatic motion during deep breathing may be a useful tool in diagnosing CPFE and in discriminating CPFE patients from IPF or COPD patients.     

Clinical Outcomes of Patients with Combined Idiopathic Pulmonary Fibrosis and Emphysema in the IPF-PRO Registry

Purpose

To assess the impact of concomitant emphysema on outcomes in patients with idiopathic pulmonary fibrosis (IPF).

Methods

The IPF-PRO Registry is a US registry of patients with IPF. The presence of combined pulmonary fibrosis and emphysema (CPFE) at enrollment was determined by investigators’ review of an HRCT scan. Associations between emphysema and clinical outcomes were analyzed using Cox proportional hazards models.

Results

Of 934 patients, 119 (12.7%) had CPFE. Compared with patients with IPF alone, patients with CPFE were older (median 72 vs 70 years); higher proportions were current/former smokers (88.2% vs 63.7%), used oxygen with activity (49.6% vs 31.9%) or at rest (30.8% vs 18.4%), had congestive heart failure (13.6% vs 4.8%) and had prior respiratory hospitalization (25.0% vs 16.7%); they had higher FVC (median 71.8 vs 69.4% predicted) and lower DLco (median 35.3 vs 43.6% predicted). In patients with CPFE and IPF alone, respectively, at 1 year, rates of death or lung transplant were 17.5% (95% CI: 11.7, 25.8) and 11.2% (9.2, 13.6) and rates of hospitalization were 21.6% (14.6, 29.6) and 20.6% (17.9, 23.5). There were no significant associations between emphysema and any outcome after adjustment for baseline variables. No baseline variable predicted outcomes better in IPF alone than in CPFE.

Conclusion

Approximately 13% of patients in the IPF-PRO Registry had CPFE. Physiologic characteristics and comorbidities of patients with CPFE differed from those of patients with IPF alone, but the presence of emphysema did not drive outcomes after adjustment for baseline covariates.

Trial registration

ClinicalTrials.gov, NCT01915511; registered August 5, 2013.

     

Combined Pulmonary Fibrosis and Emphysema Alters Physiology but Has Similar Mortality to Pulmonary Fibrosis Without Emphysema

Studies have described individuals with combined pulmonary fibrosis and emphysema (CPFE), with preserved lung volumes, significant reductions in gas exchange, and high prevalence of pulmonary hypertension. While physiologic changes in CPFE are well documented, there is little mortality data in the CPFE population compared to appropriate controls. A study was performed to determine the features and outcomes of a group of individuals with imaging and/or pathologic evidence of CPFE to determine if individuals with combined pulmonary fibrosis and emphysema have different features and survival than individuals with pulmonary fibrosis alone. We conducted a retrospective study at a Veterans Affairs Medical Center. Included in the study were individuals hospitalized over a 5-year period who were given a clinical diagnosis of pulmonary fibrosis. Individuals with confirmed imaging or pathologic evidence of pulmonary fibrosis were divided into a study group with concomitant emphysema (CPFE group, n = 20) and a control group without emphysema (isolated pulmonary fibrosis (PF) group, n = 24). The CPFE group, all current or former cigarette smokers, had significantly larger lung volumes, more expiratory airflow obstruction, and worse gas exchange than the isolated pulmonary fibrosis group. Mortality did not differ between the groups. Combined pulmonary fibrosis and emphysema results in unique physiologic features but no difference in survival compared with a group with pulmonary fibrosis alone.     

Significance of Serum Vascular Endothelial Growth Factor Level in Patients with Idiopathic Pulmonary Fibrosis

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, which has been implicated in the pathogenesis of fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF). The aim of this study was to examine the clinical significance of the serum VEGF level for evaluating disease severity and progression. The levels of VEGF in serum were measured in 41 patients with IPF, 14 patients with lung cancer, and 43 healthy volunteers. We measured the serum levels of CRP, LDH, KL-6, SP-D, and the parameters obtained from arterial blood gas analysis and pulmonary function tests. High-resolution computed tomography (HRCT) was performed to determine the extent of the interstitial and the alveolar opacities. The ability of each biomarker to predict disease severity was estimated by measuring the area under the receiver operating characteristic curve (AUC). The VEGF levels of IPF patients with high alveolar–arterial difference of oxygen (AaDO₂) levels were significantly elevated than those with low AaDO₂ levels and those of healthy volunteers. When examined within the IPF group, a significant positive correlation was found between the VEGF levels and the HRCT interstitial score (p = 0.027) and the KL-6 levels (p = 0.037). Among several serum biomarkers, VEGF showed the largest AUC for predicting disease severity as defined by a high AaDO₂ value. There was an inverse correlation between the baseline VEGF level and the monthly change in percent predicted vital capacity. The serum VEGF level may reflect the severity of IPF and offer clinical benefits to predict the disease’s progression.     

Relationship Between Quantitative CT Metrics and Pulmonary Function in Combined Pulmonary Fibrosis and Emphysema

Purpose

Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, as current reports of its clinical features show. To determine CPFE’s physiologic and radiologic features, we conducted quantitative assessment of computed tomography scans to compare with those of chronic obstructive pulmonary disease (COPD).

Methods

In 23 patients with CPFE and 42 patients with COPD, we measured the extent of emphysema (LAA %), parenchymal density, and total cross-sectional areas of pulmonary vessels smaller than 5 mm² (%CSA <5) and 5–10 mm² (%CSA 5–10).

Results

For CPFE, airflow was better, but diffusing capacity for carbon monoxide (DL_CO) was worse than for COPD, whereas LAA % was similar for both groups. The %CSA <5 was greater but %CSA5–10 was less in CPFE than COPD. COPD involved a negative correlation between DL_CO and LAA % at all lung sites; those factors correlated for CPFE only in the upper lobe (r = ?0.535). In contrast, CPFE had a negative correlation between DL_CO and parenchymal density in lower lobes (r = ?0.453), but COPD showed no correlation in any such sections. In CPFE, no correlation was apparent between LAA in upper lobes and parenchymal density in lower lobes. The annual rate of FVC decline (?169.26 ml/year) in CPFE patients correlated with parenchymal density (r = ?0.714).

Conclusions

In CPFE, fibrosis and emphysema apparently existed independently, but both correlate with and likely contribute to the disproportionate reduction in gas exchange. Our study also suggested that pulmonary fibrotic changes may be more important contributors than emphysema for disease progression.     

Combined Pulmonary Fibrosis and Emphysema With Pulmonary Hypertension: Cases Report

Background: The combination of pulmonary fibrosis and emphysema (CPFE) has been recently defined as a syndrome, it is radiologically recognized and is characterized by the simultaneous coexistence of emphysema of superior pulmonary location and fibrosis predominantly in lower lobes. Case presentation: We present three patients with CPFE, who underwent right cardiac catheterization for pulmonary hemodynamic assessment, finding mean pulmonary artery pressure (mPAP) between 37-52 mm Hg (mean 45 mm Hg), who received treatment with specific vasodilators for pulmonary arterial hypertension (PAH). Discussion and conclusions: The three patients had higher mPAP than expected for Group III (Pulmonary hypertension due to lung disease and/or hypoxia) of the classification of pulmonary hypertension (PH) by the World Health Organization (WHO), in whom the use of Sildenafil was justified by the presence of progressive dyspnea, and no symptoms suggestive of infectious exacerbation associated with right ventricular failure.     

肺纤维化合并肺气肿患者的肺功能特征

目的 了解肺纤维化合并肺气肿（combined pulmonary fibrosis and emphysema,CPFE）患者肺功能特点,及是否能通过肺功能将CPFE、单纯肺气肿、未合并肺气肿的特发性肺纤维化（idiopathic pulmonary fibrosis,IPF）进行区分.方法 回顾性分析了48例CPFE患者利用肺量计及脉冲振荡法测量的肺功能参数,并与单纯肺气肿患者（50例）、未合并肺气肿的IPF患者（46例）的肺功能进行了比较.结果 肺量计参数显示：CPFE组肺总量（TLC）％ pred正常[（86.9±17.8）％],而未合并肺气肿的IPF组TLC％ pred明显降低[（70.4±17.0）％],CPFE组的FEV1/FVC大致正常[（72.0±9.4）％],而单纯肺气肿组明显降低[（56.5±14.4）％],CPFE组、单纯肺气肿组及未合并肺气肿的IPF组的弥散功能均降低,分别为（57.2±17.3）％、（62.8±25.7）％、（66.9±21.5）％.脉冲振荡法测量的参数显示：CPFE组与未合并肺气肿的IPF组总气道阻力（R5）正常,而单纯肺气肿组明显增高[（161.3±69.0）％],虽然CPFE组、单纯肺气肿组及未合并肺气肿的IPF组外周气道阻力（R5-R20）均增加,但单纯肺气肿组较CPFE组和未合并肺气肿的IPF组增加更为明显（P=0.006,P=0.013）,三组X5轻度减低,单纯肺气肿组较CPFE组和IPF组减低更为明显（P=0.004,P=0.047）.相关分析显示：CPFE组、单纯肺气肿组R5-R20和RV/TLC呈正相关（r=0.44,P=0.01;r=0.66,P=0.01）;CPFE组、单纯肺气肿组K与RV/TLC呈负相关（r=-0.51,P=0.01; r=-0.66,P=0.01）,未合并肺气肿的IPF组TLC％ pred与R5-R20和X5有相关性（r=-0.50,P=0.01; r=0.6,P=0.01）.结论 CPFE的肺功能特点为肺容积正常,通气功能正常,弥散功能明显降低,总气道阻力及中心气道阻力正常,周边气道阻力增加和弹性阻力增高,肺的顺应性降低.     

Likelihood of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and emphysema

Background and objective

This study evaluated whether patients with combined pulmonary fibrosis and emphysema (CPFE) have an increased likelihood of pulmonary hypertension (PHT) when compared with idiopathic pulmonary fibrosis (IPF) patients without emphysema.

Methods

Two consecutive IPF populations having undergone transthoracic echocardiography were examined (n = 223 and n = 162). Emphysema and interstitial lung disease (ILD) extent were quantified visually; ILD extent was also quantified by a software tool, CALIPER. Echocardiographic criteria categorized PHT risk.

Results

The prevalence of an increased PHT likelihood was 29% and 31% in each CPFE cohort. Survival at 12 months was 60% across both CPFE cohorts with no significantly worsened outcome identified when compared with IPF patients without emphysema. Using logistic regression models in both cohorts, total computed tomography (CT) disease extent (ILD and emphysema) predicted the likelihood of PHT. After adjustment for total disease extent, CPFE had no stronger association with PHT likelihood than IPF patients without emphysema.

Conclusion

Our findings indicate that the reported association between CPFE and PHT is explained by the summed baseline CT extents of ILD and emphysema. Once baseline severity is taken into account, CPFE is not selectively associated with a malignant microvascular phenotype, when compared with IPF patients without emphysema.

     

Heterogeneous Remodeling of Lung Vessels in Idiopathic Pulmonary Fibrosis

Recently, several reports suggest differences in the vascularization of the various histopathologic patterns of parenchymal remodeling seen in usual interstitial pneumonia (UIP). In this study, we sought to validate the importance of vascular remodeling in patients with idiopathic pulmonary fibrosis (IPF) and to examine the relationship between vascular remodeling and parenchymal remodeling or pulmonary function. Open lung biopsies were performed in 57 patients with IPF, and vascular changes in alternating areas of parenchymal remodeling (UIP histologic patterns) were studied. Quantitative analysis of the internal area, internal perimeter, wall thickness, and surrounding cellularity of medium or large pulmonary arteries, as well as their distribution according to air/parenchymal ratios, was performed. Semiquantitative analysis also was used to determine the grade of vascular occlusion. An inverse association was found between vascularization and UIP parenchymal remodeling (p < 0.05); that is, the decreased internal luminal area and perimeter as well as the increased wall thickness run in parallel with progression from alveolar collapse toward severe mural-organizing fibrosis with honeycombing. Vascular regression (diminished internal area and perimeter of vessels) was also associated with higher FEV₁, FVC, and RV values (r = 0.48, p< 0.05), reflecting a tight relationship between vascular remodeling and pulmonary function. A progressive regression of vascularization, reflected by different degrees of luminal occlusion after vascular remodeling, coincided with parenchymal remodeling (alveolar collapse, mural-organizing fibrosis, and honeycombing). This vascular regression may be responsible for the impaired wound healing and progressive fibroproliferation found in patients with IPF. Further studies are needed to determine whether this relationship is causal or consequential.     

特发性肺纤维化患者支气管肺泡灌洗液和血清基质金属蛋白酶及其抑制剂检测

目的探讨特发性肺纤维化(IPF)患者支气管肺泡灌洗液(BALF)及血清中基质金属蛋白酶9(MMP9)、基质金属蛋白酶组织抑制剂1(TIMP1)水平的变化。方法2001至2004年用酶联免疫吸附(ELISA)法检测30例IPF患者BALF及血清中MMP9和TIMP1的水平,同时行肺高分辨率CT(HRCT)及肺功能检查。健康非吸烟的自愿献血者30名,为血清对照组。以胸痛为自觉症状在我院自愿进行纤维支气管镜及BALF检查,经体检及X线检查证实为健康者13名,作为BALF对照组。结果IPF患者BALF及血清中MMP9水平为(245±26)和(203±32)ng/L,对照组为(205±22)和(186±16)ng/L,两组相比差异无统计学意义;IPF组BALF及血清中TIMP1水平[(522±81)、(166±29)ng/L]高于对照组[(201±31)、(87±16)ng/L],差异有统计学意义;IPF组BALF及血清中MMP9/TIMP1比值(0.53±0.18,1.5±0.3)低于对照组(1.06±0.38,2.6±0.5)。HRCT、肺功能评分及BALF中上述指标与MMP9无明显相关性,与TIMP1呈正相关,与MMP9/TIMP1比值呈负相关。结论IPF患者肺纤维化的发生与TIMP1水平升高及MMP9/TIMP1比值降低对细胞外基质降解的抑制有关,后者可能意义更大;患者肺影像学及肺功能变化可能也与此有关。     

肺纤维化合并肺气肿的临床研究进展

特发性肺纤维化（IPF）和肺气肿在影像学、病理生理、治疗及预后等方面各不相同,是两种疾病。然而,部分患者影像学表现同时存在肺纤维化和肺气肿,被称为肺纤维化合并肺气肿（CPFE）。CPFE的表现与单纯的肺气肿或IPF不同,因此被认为是一种独立的疾病,且越来越受到关注。本文对CPFE的病因与发病机制、临床表现、诊断、并发症、治疗和预后等方面进行了综述。     

探讨TGFβ1、PDGF、VEGF对特发性肺纤维化诊断及病情评估的临床意义

目的探讨分泌转化生长因子-β、血小板衍生生长因子、血管内皮生长因子在特发性肺纤维化(IPF)患者支气管肺泡灌洗液(BALF)和血清中的表达水平及评估病情进展的临床意义。 方法选择2014年1月至2018年12月在我院呼吸科诊治的35例IPF患者作为观察组,18例肺结节病患者(Ⅰ期)作为对照组;采用免疫印迹观察TGFβ1、PDGF、VEGF在IPF患者血清中是否存在表达;用酶联免疫吸附法(ELISA)观察2组患者BALF和血清中TGFβ1、PDGF、VEGF的表达水平;最后分析IPF患者BALF和血清中TGFβ1、PDGF、VEGF表达水平与肺功能及血氧饱和度的相关性。 结果TGFβ1、PDGF、VEGF细胞印在IPF患者血清存在表达;与对照组相比,BALF及血清中的TGFβ1、PDGF、VEGF表达上调(P<0.05);IPF组患者BALF及血清中TGFβ1、PDGF、VEGF表达水平与肺功能中FVC%、FEV₁%和DLCO%呈负性相关(P<0.05);与血氧饱和度也呈显著负相关(P<0.05)。 结论IPF患者BALF和血清中TGFβ1、PDGF、VEGF的表达水平明显升高;TGFβ1、PDGF、VEGF与患者的肺功能及血氧饱和度呈负相关,可作为评估IPF患者病情的临床评价指标。     

HRCT and histopathological evaluation of fibrosis and tissue destruction in IPF associated with pulmonary emphysema

Idiopathic pulmonary fibrosis has been associated with emphysema in cigarette smokers as a new clinical entity: combined pulmonary fibrosis and emphysema (CPFE). In order to compare histomorphometrical, roentgenological and immunohistochemical aspects of usual interstitial pneumonia (UIP) with and without associated pulmonary emphysema, 17 patients with biopsy-proven UIP were evaluated. Morphometrical evaluation of lung parenchyma destruction was used to divide patients in two subgroups: emphysema/UIP (n=9) and UIP alone (n=8); four patients with biopsy-proven emphysema without fibrosis were also evaluated. At HRTC scan, emphysematous lesions were prevalent in the upper fields of both emphysema/UIP and emphysema groups and the distribution of fibrotic lesions was similar in emphysema/UIP compared to UIP alone. The semiquantitative histopathological fibrotic score was also similar in emphysema/UIP and UIP alone. In addition, the expression of tumor necrosis factor (TNF)-alpha, matrix metalloproteinase (MMP)-2, MMP-9, MMP-7 and membrane type 1-metalloproteinase (MT1-MMP) by fibroblasts of myofibroblastic foci was similar in emphysema/UIP and UIP alone patients. In contrast, fibroblasts in areas of parenchymal destruction of emphysema/UIP expressed MMP-2, MMP-9, MMP-7 and MT1-MMP at variable but significantly higher levels when compared to emphysema subjects, in the presence of similar levels of TIMP-1, TIMP-2 and TNF-alpha. Fibrotic and emphysematous lesions in emphysema/UIP patients appear to follow the roentgenological and histopathological patterns expected for either UIP or emphysema. Interstitial fibroblast activation is more pronounced in the areas of lung destruction in emphysema/UIP compared to those with emphysema alone, as for exaggerated tissue remodeling.     

成年烟雾病患者血清血管细胞黏附分子1、基质金属蛋白酶9、转化生长因子β、血管内皮生长因子水平变化及其临床意义研究

背景目前,烟雾病(MMD)的病因及发病机制尚不完全明确,此类患者通常在发生脑血管事件后才被确诊,因此探讨MMD的预测因子及评估其严重程度的指标具有重要的临床意义。目的探讨成年MMD患者血清血管细胞黏附分子1(VCAM-1)、基质金属蛋白酶9(MMP-9)、转化生长因子β(TGF-β)、血管内皮生长因子(VEGF)水平及其临床意义。方法选取2016年3月-2019年1月四川大学华西广安医院收治的成年MMD患者114例作为病例组,其中缺血型68例,出血型46例;另选取同期在本院门诊健康体检中心体检健康者30例作为对照组。比较对照组受试者体检当日与病例组患者入院第1天血清VCAM-1、MMP-9、TGF-β、VEGF水平,比较出血型与缺血型患者入院第1、7、14天血清VCAM-1、MMP-9、TGF-β、VEGF水平,并比较不同Suzuki分级成年MMD患者入院第1天血清VCAM-1、MMP-9、TGF-β、VEGF水平;成年MMD患者入院第1天血清VCAM-1、MMP-9水平与血清TGF-β、VEGF水平的相关性分析采用Pearson相关分析。结果病例组患者入院第1天血清VCAM-1、MMP-9、TGF-β、VEGF水平高于对照组(体检当日)(P<0.05)。时间与方法在血清VCAM-1、MMP-9水平上不存在交互作用(P>0.05),在血清TGF-β、VEGF水平上存在交互作用(P<0.05);时间在血清VCAM-1、MMP-9、TGF-β、VEGF水平上主效应显著(P<0.05);方法在血清VCAM-1、MMP-9水平上主效应不显著(P>0.05),在血清TGF-β、VEGF水平上主效应显著(P<0.05);出血型患者入院第1、7、14天血清TGF-β、VEGF水平高于缺血型患者(P<0.05)。Suzuki分级3级缺血型患者血清入院第1天MMP-9、VEGF水平高于Suzuki分级2级患者,Suzuki分级3级出血型患者入院第1天血清VEGF水平高于Suzuki分级2级患者(P<0.05);Suzuki分级4级缺血型、出血型患者入院第1天血清VCAM-1、MMP-9、TGF-β、VEGF水平分别高于Suzuki分级2、3级缺血型、出血型患者(P<0.05);Suzuki分级5、6级缺血型、出血型患者入院第1天血清VCAM-1、MMP-9、TGF-β、VEGF水平分别高于Suzuki分级2、3、4级缺血型、出血型患者(P<0.05);Suzuki分级6级缺血型、出血型患者入院第1天血清VEGF水平分别高于Suzuki分级5级缺血型、出血型患者(P<0.05)。Pearson相关分析结果显示,缺血型、出血型MMD患者入院第1天血清VCAM-1、MMP-9水平分别与血清TGF-β、VEGF水平呈正相关(P<0.05)。结论缺血型和出血型成年MMD患者血清VCAM-1、MMP-9、TGF-β、VEGF水平均异常升高,且均与患者病情严重程度相关;血清VCAM-1、MMP-9水平分别与缺血型、出血型MMD患者血清TGF-β、VEGF水平呈正相关,VCAM-1、MMP-9可能参与了成年MMD患者颅内出血过程。     

Sleep-Related Breathing Disorders in Patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and usually fatal lung disease of unknown etiology. The aim of this study was to describe clinical and polysomnographic features of sleep-related breathing disorders (SRBD) and to identify predictors of obstructive sleep apnea (OSA) in IPF patients. Eight hundred fifty-seven patients with IPF were admitted to the Cleveland Clinic from 2001 to 2005. An all-night polysomnogram (PSG) was performed in 18 of them to investigate complaints suggestive of sleep-disordered breathing. OSA was confirmed in 11 of the 18 IPF patients with complaints suggestive of sleep apnea, while the remain 7 patients had a diagnosis of primary snoring or upper airway resistance syndrome (UARS). All patients showed a reduction in sleep efficiency, REM sleep, and slow wave sleep. The apnea-hypopnea index (AHI) was positively correlated with body mass index (p < 0.0001, r = 0.80). The REM AHI and overall AHI were negatively correlated with FEV₁ (p = 0.008, r = −0.59 and p = 0.04, r = −0.49, respectively) and FVC percentages (p = 0.03, r = −0.50 and p = 0.08, r = −0.42, respectively). Our study is the first describing SRBD in IPF patients. An increased BMI and a significant impairment in pulmonary function testing may be predictors of OSA in this population. In the absence of effective treatments for IPF, the diagnosis and treatment of comorbid SRBD may lead to improvements in quality of life.     

肺纤维化合并肺气肿综合征:呼吸内科临床的“新问题”

部分吸烟者胸部高分辨率CT显示,上肺野为主的肺气肿和下肺野为主的纤维化表现同时存在,目前认为这是一类独立的疾病,称作肺纤维化合并肺气肿(CPFE)综合征。其发病机制不详。患者肺功能表现为肺容积相对正常或者轻度异常然而弥散能力显著下降,因此CPFE严重程度评价不同于慢性阻塞性肺疾病和(或)肺气肿或者特发性肺纤维化。CPFE肺动脉高压发生率显著高于慢性阻塞性肺疾病和(或)肺气肿或者肺纤维化患者、并且与预后不良有关。常规支气管扩张剂及糖皮质激素治疗效果欠佳,值得呼吸科医生关注。     

晚期血吸虫病肝纤维化指标与肝组织病理学的相关性研究、

目的探讨转化生长因子-β1（TGF-β1）、基质金属蛋白酶-1（MMP-1）及其组织抑制因子-1（TIMP-1）在晚期血吸虫病（晚斑）肝组织和血清中的表达及其与肝组织病理学的关系。方法采用免疫组化sP法检测45例晚血（观察组）肝组织中TGF-β1、MMP-1、TIMP-1表达;采用EIASA法检测观察组和30例健康人（对照组）血清TIMP-1、TGF-β1、MMP-1水平。结果观察组肝组织中TGF-β1、TIMP-1表达强度与肝纤维化程度、有无合并HBV感染呈正相关（P均〈0．05）;而MMP-1无相关性。与对照组比较,观察组血清TGF-β1、TIMP-1水平及TIMP-1／MMP-1值明显增高（P均〈0．01）,并与肝纤维化程度、免疫组化表达强度呈正相关（P均〈0．01）,而血清MMP-1差异无统计学意义。结论TGF-β1、MMP-1、TIMP-1与晚血肝纤维化的发生、发展密切相关,三者联合检测可作为晚血患者肝纤维化诊断和疗效评估指标。     

N-acetyl-l-cysteine inhibits TGF-β1-induced profibrotic responses in fibroblasts

BackgroundExcessive production of TGF-β₁ plays a key role in the tissue remodeling or fibrotic process observed in bronchial asthma, chronic pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). TGF-β₁ has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species.ObjectivesThe aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine (NAC) can affect TGF-β₁-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor (VEGF) which are believed to be important mediators of tissue repair and remodeling.MethodsTo accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the effect of NAC on the TGF-β₁-mediated contraction of floating gels and the TGF-β₁-induced mediator production. In addition, the effect of NAC on the TGF-β₁-induced differentiation to myofibroblasts was evaluated by assessing α-smooth muscle actin (α-SMA) expression.ResultsNAC significantly abolished the TGF-β₁-augmented gel contraction (at 3 mM, gel size 63.4 ± 2.6% vs. 39.1 ± 4.1%; p < 0.01) compared with control in a concentration-dependent manner. NAC also significantly inhibited the TGF-β₁-augmented fibronectin (p < 0.01) and VEGF (p < 0.01) production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the TGF-β₁-stimulated α-SMA expression (p < 0.01).ConclusionThese results suggest that NAC can affect the TGF-β₁-induced tissue remodeling or fibrotic process in vitro.