Exercise capacity in idiopathic pulmonary fibrosis: the effect of pulmonary hypertension

Background and objective: Increased pulmonary arterial pressure (PAP) usually coexists with impaired lung function in IPF. Data on the effect of pulmonary hypertension (PH) on cardiopulmonary responses during exercise in IPF patients is very limited. We sought to investigate the impact of PH on exercise capacity and the correlation between systolic PAP (sPAP) and pulmonary function testing, as well as cardiopulmonary exercise parameters, in patients with IPF and PH. Methods: Eighty‐one consecutive patients with IPF, who were evaluated over a 6‐year period, were retrospectively studied. Patients underwent pulmonary function testing, Doppler echocardiography and maximal cardiopulmonary exercise testing. PH was defined as sPAP > 35 mm Hg. Results: PH was diagnosed in 57% of the patients. Categorization of patients according to severity of PH indicated a significant reduction in maximum work rate, peak O₂ uptake, anaerobic threshold and peak O₂ pulse in those with sPAP > 50 mm Hg. In IPF patients with PH, estimated sPAP correlated with peak O₂ uptake, anaerobic threshold, peak O₂ pulse and end‐tidal CO₂ at anaerobic threshold, while the strongest correlation was between sPAP and ventilatory equivalent for CO₂ at anaerobic threshold (r = 0.611, P < 0.001). There were no differences in pulmonary function or exercise parameters indicative of lung volume reduction, across the patient categories, and none of these parameters correlated with sPAP. Conclusions: PH has a negative impact on exercise capacity in IPF patients. In IPF patients with PH, resting sPAP correlated with exercise parameters indicative of gas exchange and circulatory impairment, but not with defective lung mechanics.     

转录因子AP-1在慢性阻塞性肺疾病中的作用

目的探讨慢性阻塞性肺疾病（COPD）炎症发生的分子生物学机制。方法对12例COPD患者（COPD组）、10例支气管哮喘患者（哮喘组）、10例健康成年人（对照组）采用免疫细胞化学和逆转录-聚合酶链反应技术,检测其外周血单个核细胞（PBMC）中转录因子激活蛋白AP-1（c-fos和c-jun）及白细胞介素8（IL-8）的表达水平。结果c-fos表达在COPD组和哮喘组之间无显著性差异,但均高于对照组（P〈0．05）。c-jun、IL-8的表达在COPD组明显高于其他两组（P〈0．05）,且c-jun与IL-8的表达呈明显正相关。结论c-jun的高表达在COPD的慢性炎症过程中具有重要作用,高表达的c-jun可能使AP-1活性增强,促进IL-8表达升高。     

External validation of the GAP model in Chinese patients with idiopathic pulmonary fibrosis

Introduction

The GAP model was widely used as a simple risk “screening” method for patients with idiopathic pulmonary fibrosis (IPF).

Objectives

We sought to validate the GAP model in Chinese patients with IPF to evaluate whether it can accurately predict the risk for mortality.

Methods

A total of 212 patients with IPF diagnosed at China-Japan Friendship Hospital from 2015 to 2019 were enrolled. The latest follow-up ended in September 2022. Cumulative mortality of each GAP stage was calculated and compared based on Fine-Gray models for survival, and lung transplantation was treated as a competing risk. The performance of the model was evaluated in terms of both discrimination and calibration.

Results

The cumulative mortality in patients with GAP stage III was significantly higher than that in those with GAP stage I or II (Gray's test p < 0.0001). The Harrell c-index for the GAP calculator was 0.736 (95% CI: 0.667–0.864). The discrimination for the GAP staging system were similar with that for the GAP calculator. The GAP model overestimated the mortality rate at 1- and 2-year in patients classified as GAP stage I (6.90% vs. 1.77% for 1-year, 14.20% vs. 6.78% for 2-year).

Conclusions

Our findings indicated that the GAP model overestimated the mortality rate in mild group.     

Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance

BACKGROUND: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is thought to effect an anti-inflammatory response, but its mechanism is still unknown. METHODS: eNOS transgenic (eNOS-TG) mice and their littermate controls (C57/BL6) were used to clarify the role of NO derived from eNOS. Bleomycin hydrochloride (1 U/body/day) or PBS was injected intraperitoneally. RESULTS: Subpleural fibrotic changes and hydroxyproline content in the eNOS-TG mice were significantly reduced compared with those of the wild-type (WT) mice by day 56. Administration of N(omega)-nitro-L-arginine methyl ester, a potent inhibitor of NO synthase, worsened the fibrotic response in bleomycin-treated eNOS-TG mice. Gelatinolytic activity in lung homogenates, corresponding to metalloproteinase-9 (MMP-9), was significantly increased in bleomycin-injured WT mice on day 14. In contrast, the level of tissue inhibitor of metalloproteinases-1 (TIMP-1), an endogenous MMP-9 inhibitor, was increased in the bleomycin-treated eNOS-TG mice compared with WT. Immunohistochemical analysis demonstrated that MMP-9 and TIMP-1 were strongly expressed in inflammatory cells, including subpleural fibrotic lesions. CONCLUSION: These data suggested that eNOS overexpression attenuates bleomycin-induced lung injury by ameliorating the MMP-9/TIMP-1 balance.     

Marked elevation of CA19-9 in a patient with idiopathic pulmonary fibrosis: CA19-9 as a bad prognostic factor

Abstract A 53-year-old Japanese female, who had been suffering from idiopathic pulmonary fibrosis (IPF) for 3 years, was admitted with dyspnoea. The important laboratory finding on admission was a serum CA19-9 level of 649 U/mL. Despite steroid treatment for IPF, her respiratory condition gradually deteriorated with the increase of serum CA19-9 level up to 3020 U/mL and she died of respiratory failure. Immunohistochemistry showed the positive stain of CA19-9 in bronchoepithelial cells. We also reviewed the Index Medics and picked up the cases who had elevation of CA19-9 more than 1000 U/mL, and six patients were listed. Five of these six patients died within 6 months, therefore the marked elevation of CA19-9 seemed to be a bad prognostic factor in patients with pulmonary fibrosis.     

Aspirin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing the ERK/MAPK pathway

This study aimed to investigate the therapeutic effects of aspirin (ASA) and its potential mechanisms of action in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. PAH was induced in a rat model by a single intraperitoneal (IP) injection of MCT. Saline was injected in a control group. Two weeks following MCT injection, right ventricular systolic pressure (RVSP) and systolic blood pressure (SBP) were measured in six rats from each group to confirm establishment of a PAH model. The remaining MCT-treated rats were randomly allocated to receive IP injection of saline, ASA, or ERK1/2 inhibitor PD98059. Four weeks following treatment, RVSP was measured and all rats were sacrificed for histological study. There was no significant difference in SBP in any group two weeks following MCT administration. Nonetheless RVSP was significantly increased in the MCT group compared with the control group. At 6 weeks, ASA treatment remarkably attenuated MCT-induced increased RVSP, RV hypertrophy, and pulmonary artery remodeling compared with the MCT group. The density of pulmonary capillaries in ASA-treated rats was also dramatically increased. Treatment with ASA significantly inhibited the increased p-ERK1/2 and restored the impaired endothelial nitric oxide synthase (eNOS) in MCT-treated rats. This study demonstrated that ASA distinctively attenuates MCT-induced PAH by inhibition of the ERK1/2 signaling pathway.     

Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway

The intracellular signaling mechanisms underlying postnatal angiogenesis are incompletely understood. Herein we show that Grb-2-associated binder 1 (Gab1) plays a critical role in ischemic and VEGF-induced angiogenesis. Endothelium-specific Gab1 KO (EGKO) mice displayed impaired angiogenesis in the ischemic hindlimb despite normal induction of VEGF expression. Matrigel plugs with VEGF implanted in EGKO mice induced fewer capillaries than those in control mice. The vessels and endothelial cells (ECs) derived from EGKO mice were defective in vascular sprouting and tube formation induced by VEGF. Biochemical analyses revealed a substantial reduction of endothelial NOS (eNOS) activation in Gab1-deficient vessels and ECs following VEGF stimulation. Interestingly, the phosphorylation of Akt, an enzyme known to promote VEGF-induced eNOS activation, was increased in Gab1-deficient vessels and ECs whereas protein kinase A (PKA) activity was significantly decreased. Introduction of an active form of PKA rescued VEGF-induced eNOS activation and tube formation in EGKO ECs. Reexpression of WT or mutant Gab1 molecules in EGKO ECs revealed requirement of Gab1/Shp2 association for the activation of PKA and eNOS. Taken together, these results identify Gab1 as a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on PKA. Of note, this pathway is conserved in primary human ECs for VEGF-induced eNOS activation and tube formation, suggesting considerable potential in treatment of human ischemic diseases.     

Significance of lung shrinkage on CXR as a prognostic factor in patients with idiopathic pulmonary fibrosis

OBJECTIVE: The aim of this study was to determine whether the presence of lung shrinkage on CXR can predict diminished survival in patients with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). METHODOLOGY: In a hospital-based cohort study 68 subjects diagnosed with IPF/UIP by surgical lung biopsy or at autopsy were observed for a mean of 7.6 years. The radiographic scores from Cherniack's method, pulmonary function tests, arterial blood gas, and haematological data were obtained at initial presentation. Longitudinal radiographic changes over a mean interval of 2.7 years were measured. Survival analysis was performed using Kaplan-Meier and Cox's proportional hazards regression analysis. RESULTS: At some point during the observation period 36 (53%) of 68 patients did not exhibit lung shrinkage and 32 (47%) of 68 patients showed lung shrinkage. Patients with lung shrinkage were more likely to have a diminished survival than those with lung preservation; median survival was 4.4 vs 7.8 years, respectively. Lung shrinkage during the observation period (hazard ratio, 3.89; 95% CI = 1.68-9.01; P= 0.001) was associated with lower rates of survival. CONCLUSION: In patients with IPF/UIP, lung shrinkage on CXR during the observation period was a poor prognostic factor.