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.

     

Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema

BACKGROUND: Pulmonary emphysema, a major component of COPD, is pathologically characterized by destructive alterations in pulmonary architectures as a result of persistent inflammation. However, alterations in the turnover of pulmonary cells are less well understood. This study was designed to examine whether the turnover of alveolar wall cells is altered in patients with emphysema. PATIENTS AND MEASUREMENTS: We obtained lung tissue specimens from patients with emphysema who had undergone lung volume reduction surgery (13 patients) as well as asymptomatic smokers (7 patients) and nonsmokers (9 patients) undergoing lung resections for solitary lung cancers. Paraffin-embedded lung tissue sections were evaluated for apoptosis and proliferation using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) or immunohistochemistry for Bax, proliferation cell nuclear antigen (PCNA), and topoisomerase IIalpha. Tissue sections were also immunostained for epithelial membrane antigen, surfactant protein A, and CD31. RESULTS: The percentages of alveolar wall cells undergoing apoptosis and proliferation of the total number of alveolar wall cells were significantly higher in patients with emphysema than in asymptomatic smokers and nonsmokers (p < 0.05). The percentage of TUNEL-positive alveolar wall cells was positively correlated with the percentage of PCNA-positive alveolar wall cells. Most of the TUNEL-positive and PCNA-positive cells were alveolar epithelial cells. CONCLUSIONS: These results suggest that the turnover of alveolar wall cells is enhanced in emphysematous lungs, compared to healthy lungs. Emphysema may be a dynamic disease process in which alveolar wall cell death and proliferation are repeated.     

Estimating pulmonary artery pressures by echocardiography in patients with emphysema.

In patients with emphysema being evaluated for lung volume reduction surgery, Doppler echocardiography has been used to screen for pulmonary hypertension as an indicator of increased peri-operative risk. To determine the accuracy of this test, the present authors compared the results of right heart catheterisations and Doppler echocardiograms in 163 patients participating in the cardiovascular substudy of the National Emphysema Treatment Trial. Substudy patients had both catheterisation and Doppler echocardiography performed before and after randomisation. In 74 paired catheterisations and echocardiograms carried out on 63 patients, the mean values of invasively measured pulmonary artery systolic pressures and the estimated right ventricular systolic pressures were similar. However, using the World Health Organization's definitions of pulmonary hypertension, echocardiography had a sensitivity of 60%, specificity of 74%, positive predictive value of 68% and a negative predictive value of 67% compared with the invasive measurement. Bland-Altman analysis revealed a bias of 0.37 kPa with 95% limits of agreement from -2.5-3.2 kPa. In patients with severe emphysema, echocardiographic estimates of pulmonary artery pressures correlate very weakly with right heart catheterisations, and the test characteristics (e.g. sensitivity, specificity, etc.) of echocardiographic assessments are poor.     

Significance of pulmonary artery pressure in emphysema patients with mild-to-moderate hypoxemia

The guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) do not recommend the measurement of pulmonary artery pressure in patients with chronic obstructive pulmonary disease (COPD). This is on the basis that the mean pulmonary artery pressure (mPAP) does not provide more clinical information than measurement of the oxygen tension in arterial blood (PaO2). The mPAP correlates well with PaO2 in emphysema patients with severe hypoxemia (PaO2 < or = 7.3 kPa (55 mmHg)). However, the occurrence and significance of mPAP is unclear in patients without severe hypoxemia (PaO2 > 7.3 kPa (55 mmHg)). In order to evaluate the usefulness of measurement of mPAP in emphysema patients without severe hypoxemia, we performed right heart catheterization and investigated the pulmonary hemodynamics of 53 patients without severe hypoxemia. In addition, we identified long-term prognostic factors with a mean follow-up term of 77 months after right heart catheterization. Seventeen of 27 patients with mild-to-moderate hypoxemia exhibited pulmonary hypertension (mPAP > or = 2.7 kPa (20 mmHg)) and the classification according to severity in GOLD exhibited a greater correlation to mPAP than PaO2. Moreover, only mPAP was found to be a significant prognostic factor according to multivariate proportional hazards analysis (P = 0.01). We conclude that mPAP is more informative about the severity of emphysema than PaO2 in patients with mild-to-moderate hypoxemia.     

In contrast to lung fibroblasts--no signs of senescence in skin fibroblasts of patients with emphysema

Smoking is known to be linked to skin ageing and there is evidence for premature senescence of parenchymal lung fibroblasts in emphysema. To reveal whether the emphysema-related changes in cellular phenotype extend beyond the lung, we compared the proliferation characteristics of lung and skin fibroblasts between patients with and without emphysema. Parenchymal lung fibroblasts and skin fibroblasts from the upper torso (thus limiting sun exposure bias) were obtained from patients without, or with mild, or with moderate to severe emphysema undergoing lung surgery. We analysed proliferation rate, population doublings (PD), staining for senescence-associated beta-galactosidase (beta-gal) and gene expression of IGFBP-3 and IGFBP-rP1. Population doubling time of lung fibroblasts differed between control, mild, and moderate to severe emphysema (median (IQR) 29.7(10.0), 33.4(6.1), 44.4(21.2) h; p=0.012) and staining for beta-gal was elevated in moderate to severe emphysema. Compared to control subjects, skin fibroblasts from patients with emphysema did not differ with respect to proliferation rate, PD and beta-gal staining, and showed a lower abundance of mRNA for IGFBP-3 and -rP1 (p<0.05, each). These results suggest that the induction of a senescent fibroblast phenotype by cigarette smoke, as observed in emphysema, primarily occurs in the lung.     

Alveolar macrophages and emphysema in surfactant protein-D-deficient mice

Abstract:   Surfactant protein-D (SP-D) is a member of the collectin family of collagenous proteins with lectin activity. SP-D is expressed in numerous tissues, primarily in type II alveolar cells in the periphery of the lung. SP-D plays an important role in host defense of the lung. To evaluate the importance of SP-D in vivo , transgenic mice lacking SP-D (SP-D-/- mice) have been generated. Lipid accumulation and airspace enlargement were observed in the lungs of SP-D-/- mice within 3 weeks after birth, and progressed with advancing age. Airspace enlargement and abnormalities in elastin fibers supported the concept that SP-D was required to inhibit destruction of the alveoli. Alveolar macrophages from SP-D-/- mice produced more H₂O₂ and matrix metalloproteinases (MMP)-2, -9, and -12 compared with wild-type mice. In vitro studies demonstrated that oxidants derived in part from NADPH oxidase enhanced NF-κB activation and MMP production in alveolar macrophages from SP-D-/- mice. A specific inhibitor of NF-κB reduced MMP production by alveolar macrophages from SP-D-/- mice. Taken together, these data demonstrated oxidant-dependent activation of NF-κB and enhanced MMP expression by alveolar macrophages from SP-D-/- mice, a process likely to mediate airspace remodeling caused by SP-D deficiency. SP-D plays a critical role in regulating alveolar macrophage activation, oxidant production, and MMP activity that may influence the pathogenesis of various pulmonary disorders.     

肺泡巨噬细胞在慢性阻塞性肺疾病气道炎症中的作用

目的探讨肺泡巨噬细胞(AM)在慢性阻塞性肺疾病(COPD)气道炎症中的作用.方法收集支气管肺泡灌洗液(BALF)和支气管黏膜,用ELISA法测定BALF和AM培养上清液中巨噬细胞炎症蛋白(MIP)-lα、明胶酶B(MMP-9)及白细胞介素(IL)-8的浓度,用放射免疫法测内皮素(ET)浓度,用免疫组化法测BALF中淋巴细胞功能相关抗原1阳性(LFA-1+)AM数、黏膜内CD+/68细胞数和气道黏膜厚度.结果COPD组AM培养上清液中MIP-1α、MMP-9、ET、IL-8的浓度分别为(1446.9±126.7)μg/L、(16.98±5.15)μg/L、(43.98±5.54)ng/L、(168.10±21.22)μg/L,正常对照组为(1123.5.5±90.6)μg/L、(5.24±0.93)μg/L、(25.99±6.05)ng/L、(124.68±9.96)μg/L;COPD组支气管黏膜内CD+/68细胞数为(1.71±0.48)细胞/Hp,正常对照组为(0.59±0.18)细胞;COPD组支气管黏膜厚度为(1.96±0.96)×100-μm,正常对照组为(0.83±0.43)×10-1μg;两组比较差异均有显著性.BALF中AM数、AM培养上清液中MMP-9及ET的浓度、黏膜内CD+/68细胞数均与1秒钟用力呼气容积(FEV1)占预计值的百分比呈负相关(r=-0.511,P《0.01;r=-0.678,P《0.01;r=-0.871,P《0.01;r=-0.588,P《0.01);BALF中MIP-1α浓度、IFA-1+AM数与AM数呈正相(r=0.572,P《0.01;r=0.625,P《0.01).结论AM在COPD气道炎症和气道重建的发展过程中可能具有重要作用.     

The prevalence of pulmonary fibrosis combined with emphysema in patients with lung cancer

Background and objective: Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder of the upper lobe, whereas emphysema is usually associated with lower lobe fibrosis. Although CPFE might increase the risk of lung cancer, the prevalence of CPFE in patients with lung cancer and the incidence of lung cancer in patients with CPFE are unknown. The objective of this study was to determine the prevalence of CPFE in lung cancer patients and to assess the clinical features of these patients. Methods: A total of 1143 patients with lung cancer were reviewed. Based on HRCT performed at diagnosis of lung cancer, patients were categorized into four groups: normal, emphysema, fibrosis and CPFE. The clinical characteristics of patients with CPFE were compared with those of the other groups. Results: CPFE, emphysema and fibrosis were identified in 101 (8.9%), 404 (35.3%) and 15 (1.3%) patients with lung cancer, respectively. The median overall survival of CPFE patients (n = 101, 10.8 months) was significantly less than that of normal patients (n = 623, 53.0 months) or that of patients with emphysema alone (n = 404, 21.9 months). Acute lung injury occurred in 20 (19.8%) patients with CPFE. Conclusions: CPFE is more prevalent than fibrosis in patients with lung cancer, and patients with CPFE had a poorer prognosis in the present study. Further investigation is therefore necessary to elucidate whether CPFE is an independent risk factor for lung cancer.