non-IPF Patients Research Articles

Usual interstitial pneumonia and smoking-related interstitial fibrosis display epithelial to mesenchymal transition in fibroblastic foci

Fibroblastic foci (FF) are a major histological feature of usual interstitial pneumonia (UIP) in idiopathic pulmonary fibrosis (IPF) and collagen vascular diseases (non-IPF). In addition, FF are occasionally associated with smoking-related interstitial fibrosis (SRIF). Recent studies have suggested a role for epithelial to mesenchymal transition (EMT) in pulmonary fibrogenesis. Here, we investigated whether EMT was present in patients with IPF (n=19), non-IPF (n=17), and SRIF (n=16) using morphometric immunohistochemistry, electron microscopy, and confocal microscopy. All patients had received lung biopsies or lobectomies for lung cancer. IPF and non-IPF patients displayed restrictive lung function patterns, whereas those with SRIF presented mixed patterns. Cells within FF presented high number of alpha-smooth muscle actin (αSMA)-staining cells; however, the foci of IPF patients showed comparatively lower number. Moreover, colocalization of thyroid transcription factor-1 (TTF1) and αSMA within FF showed low number of staining cells for IPF and SRIF in comparison to non-IPF (p<0.01). Nevertheless, all groups displayed colocalization of high rate of TTF1(+)-cells and low rate of αSMA(+)-cells within hyperplastic epithelioid cells in FF. Also, we observed areas with low proportion of TTF1(+)cells and αSMA(+)cells, which were present in SRIF and non-IPF more often than IPF (p<0.001). Electron microscopy revealed small breaks in the alveolar basal lamina, which allowed epithelioid cells to directly contact the collagenous matrix and fibroblasts. Three-dimensional reconstruction revealed intense αSMA staining within some epithelioid cells, suggesting that they had gained a mesenchymal phenotype. These findings constitute the first report of EMT in SRIF and suggest that EMT occurs more prominently in SRIF and non-IPF than IPF.

The Multicenter Study of a New Assay for Simultaneous Detection of Multiple Anti-Aminoacyl-tRNA Synthetases in Myositis and Interstitial Pneumonia

ObjectiveAutoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren’s syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP.

Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients

The aim of the study was to characterise gastro-oesophageal reflux (GOR) in idiopathic pulmonary fibrosis (IPF). 40 consecutive IPF patients underwent pulmonary high-resolution computed tomography (HRCT) scan and impedance-pH monitoring while off antisecretory therapy. The presence of pulmonary fibrosis was assessed using validated HRCT scores. Reflux features included distal oesophageal acid exposure, number of acid/weakly acidic reflux episodes and their proximal migration. 40 consecutive patients with interstitial lung disease other than IPF (non-IPF patients) and 50 healthy volunteers were also enrolled. IPF patients had significantly higher (p<0.01) oesophageal acid exposure (median (interquartile range (IQR)) 9.25 (4.7-15.4)% versus 3.3 (1.4-7.4)% versus 0.7 (0.2-4.2)%, number of acid (median (IQR) 45 (23-55) versus 32 (19-44) versus 18 (10-31)), weakly acidic (median (IQR) 34 (19-43) versus 21 (11-33) versus 18 (15-28)) and proximal reflux (median (IQR) 51 (26.5-65.5) versus 20 (9.5-34.5) versus 9 (5-20)) events compared to non-IPF patients and healthy volunteers, respectively. Pulmonary fibrosis HRCT scores correlated well with reflux episodes in both the distal (r(2)=0.567) and proximal (r(2)=0.6323) oesophagus. Patients with IPF had more bile acids and pepsin (p<0.03) in bronchoalveolar lavage fluid (BALF) (62% and 67%, respectively) and saliva (61% and 68%, respectively) than non-IPF patients (25% and 25% in BALF, and 33% and 36%, respectively, in saliva) and controls (0% and 0% in BALF and saliva, respectively). Acid GOR is common in IPF, but weakly acidic GOR may also occur. Patients with IPF had a risk of pulmonary aspiration of gastric contents. Outcome studies with intense antireflux therapy are needed.

477 Clinical Implications of Impedance Monitoring in Suspected Extraesophageal Reflux: Can the Traditional Physiologic Parameters Predict Impedance Results?

LES resting pressure compared to non-IPF patients (14.1 [4-32.5] vs. 16.7 [4-37.2]; p= 0.0999). Mean contraction amplitude in the distal and proximal esophagus were slightly higher in IPF compared to non-IPF patients (92.4 [40-190] vs. 84 [35-170] and 90.6 [10210] vs. 79.9 [10-210], respectively; p=ns), but the difference was not significant. In contrast, IPF patients had significantly higher (p<0.01) esophageal acid exposure (9.25[4.7-15.4] vs. 3.3[1.4-7.4] vs. 0.7[0-2.4.2]), number of acid (45[23-55] vs. 32[19-44] vs. 18[10-31]), weakly-acidic (34[19-43] vs. 21[11-33]) vs. 18[15-28]) and proximal reflux events (51[26.565.5] vs. 20[9.5-34.5] vs. 9[5-20]) compared to non-IPF patients and HVs. Pulmonary fibrosis HRCT-scores correlated well with reflux episodes in both distal (r2=0.567) and proximal (r2=0.6323) esophagus. Patients with IPF had more bile acids and pepsin (p<0.001) in BAL (62% and 67%) and saliva (61% and 68%) than non-IPF patients (40% and 40% in BAL, 33% and 36% in saliva) and controls (0% and 0% in both BAL and saliva). Conclusion: Increased acid and weakly acidic GER as well as more reflux reaching the proximal esophagus are prevalent in IPF. Patients with IPF have a relevant risk of gastric aspiration (increased bile acids and pepsin in saliva) or definite gastric aspiration (bile acids or pepsin in BAL). Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in IPF progression.

Short-term outcomes of lung transplant in idiopathic pulmonary fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is currently the main indication for lung transplant (LTx) in the United States. Opinions differ regarding the outcomes in IPF compared to other conditions. This study compares the short-term outcomes of LTx in IPF versus non-IPF as well as single lung transplant (SLT) versus bilateral lung transplant (BLT) in IPF patients in a large nationally representative sample. METHODS: We performed a secondary analysis of the Nationwide Inpatient Sample (1988–2006). Patients aged 21 and above who underwent LTx during this period were included. The five post-operative outcomes evaluated were inpatient mortality (IM), transplant-related complications (TC), non-transplant related (NTC) complications during inpatient stay, length of stay (LOS) more than 14 days and any non-routine discharge (ND) destination. RESULTS: There were 1845 patients who underwent LTx during the analysis period. Controlling for confounders, and compared to non-IPF patients, IPF patients were more likely to be in hospital more than 14 days (OR = 1.75; 95% CI = 1.31, 2.36; p ≤ 0.001); as likely to have inpatient mortality (OR = 1.00; 95% CI = 0.58, 1.72) and non-routine discharge (OR = 0.95; 95% CI = 0.73, 1.50); and not significantly less likely to have transplant-related complications (OR = 0.82; 95% CI = 0.57, 1.17) and non-transplant related complications (OR = 0.89; 95% CI = 0.65, 1.22). IPF patients who underwent BLT were significantly more likely to develop transplant-related complications (OR = 2.52; 95% CI = 1.06, 5.97; p = 0.035) and non-transplant related complications (OR = 2.22; 95% CI = 1.17, 4.24; p = 0.015); and not significantly more likely to have inpatient mortality (OR = 2.24; 95% CI = 0.80, 6.27), length of stay longer than 14 days (OR = 1.84; 95% CI = 0.83, 4.11) and non-routine discharge (OR = 1.15; 95% CI = 0.44, 1.69). CONCLUSIONS: This paper demonstrated that in this population of patients in the United States, there was an increased risk of greater LOS for IPF patients. BLT in IPF patients had a significantly higher risk for inpatient complications.

Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis

Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling. Our previous study suggested that SOCS1 regulates collagen synthesis by lung fibroblasts, suggesting a role of SOCS1 in the pathophysiology of pulmonary fibrosis. We sought to investigate the role of SOCS1 in pulmonary inflammation and fibrosis in vivo. SOCS1-haplodeficient mice treated with bleomycin (BLM) were evaluated for pulmonary inflammation and fibrosis compared with wild-type mice. The human study group was composed of 18 patients with interstitial lung disease. Lung specimens obtained by means of open lung biopsy were investigated to determine whether the severity of fibrosis was associated with decreased SOCS1 expression. Finally, we further analyzed the effect of exogenous SOCS1 on BLM-induced lung injury based on adenoviral SOCS1 gene transfer to the lung. SOCS1-haplodeficient mice treated with BLM showed markedly enhanced pulmonary inflammation and fibrosis compared with wild-type mice. Using human lung specimens, we found that SOCS1 mRNA levels inversely correlated with duration of the disease. SOCS1 expression was significantly less in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) compared with that in non-IPF patients. Moreover, SOCS1 expression was significantly less in severe fibrotic lesions (lower lobe) than in less fibrotic lesions (upper lobe). Adenoviral SOCS1 gene transfer to murine lungs significantly decreased lymphocytic inflammation, pulmonary fibrosis, and mortality because of BLM-induced lung injury. Exogenous SOCS1 inhibited expression of various cytokines, including TNF-alpha, which might play a key role. These results suggest that SOCS1 might act as a suppressor for pulmonary fibrosis. SOCS1 might be a target of IPF treatment.

Positron emission tomography in interstitial lung disease

A high rate of glycolysis may reflect the inflammatory activity of interstitial lung disease (ILD). This prospective study investigated whether PET can distinguish IPF, a primarily fibrotic process, from other entities of ILD that have a marked inflammatory component. Twenty-one patients referred for surgical lung biopsy because of diffuse ILD underwent PET at the time of the lung biopsy. PET transmission scans were obtained after injecting (18)FDG intravenously. Regions of interest (ROI) were drawn on the lung images, and the standardized uptake value (SUV) was calculated for these ROI. Of the 21 patients studied, 14 had IPF, four had non-specific interstitial pneumonia, and the remaining three patients each had respiratory bronchiolitis-ILD, sarcoidosis and Langerhan's cell histiocytosis. There was no statistically significant difference in the SUV between IPF patients and non-IPF patients (P = 0.26), although patients with IPF tended to have higher SUV. Radiographic changes tended to be more prominent in the lung bases in patients with IPF compared with non-IPF patients; however, the median ratio of SUV measured in the upper fields to the whole lungs in IPF patients was not significantly different compared with the median ratio in non-IPF patients (P = 0.31). PET does not allow differentiation of IPF from a non-IPF diffuse interstitial pulmonary process.

Lung Transplantation for Idiopathic Pulmonary Fibrosis

Outcomes of lung transplantation for idiopathic pulmonary fibrosis (IPF) are thought to be worse than those for other indications, although the reasons are unknown. In addition, the choice of single versus double lung transplantation is unclear. To guide decision-making, we (1) compared survival of patients receiving transplantation for IPF with survival of patients receiving transplantation for non-IPF diagnoses, (2) identified risk factors for mortality after transplantation for IPF, and (3) ascertained whether double lung transplantation for IPF confers a survival advantage. From February 1990 to November 2005, 469 patients underwent lung transplantation, 82 for IPF. Multiphase hazard modeling was used to identify risk factors, and propensity matching was used to compare survival of IPF and non-IPF patients and to assess the effect of single versus double lung transplantation. Survival estimates after transplantation for IPF were 95%, 73%, 56%, and 44% at 30 days and 1, 3, and 5 years, somewhat worse than for matched non-IPF patients (p = 0.03). Risk factors for mortality were earlier date of transplantation (p = 0.07), single lung transplantation (p = 0.03), and higher wedge pressure (p = 0.003). Survival for double versus single lung transplantation was 81% versus 67% at 1 year and 55% versus 34% at 5 years; however, among matched non-IPF patients, corresponding survivals were 88% versus 71% at 1 year and 72% versus 48% at 5 years (p = 0.3). Survival after lung transplantation for IPF is worse than after other indications for transplantation when multiple clinical variables are accounted for. Survival may be improved by double lung transplant.

Idiopathic Pulmonary Fibrosis

In this issue of Seminars, we have assembled an internationally renowned group of clinicians and scientists to discuss current controversies and evolving concepts in idiopathic pulmonary fibrosis (IPF). Over the past 5 years, the implementation of an improved classification system of the idiopathic interstitial pneumonias (IIPs) has helped to define subgroups of non-IPF patients who carry more favorable prognoses and are more likely to respond to currently available therapies.[1] IPF, the most common of the IIPs, remains enigmatic and no effective therapies currently exist. Our panel of experts outlines current concepts and controversies regarding pathogenesis, diagnosis, and management of patients with IPF.

Discoidin Domain Receptor 1 Contributes to the Survival of Lung Fibroblast in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-kappaB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappaB nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-kappaB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.

Etiologic Distribution, Diagnostic Tests and Treatment in Prospectively Registered Patients with DILD for Two Years in a Tertiary Medical Center

Introduction : Diffuse interstitial lung diseases (DILD) comprise of a large group of lung diseases with diverse etiologies. They are classified into four categories based on the etiology and pathological findings. In Korea, epidemiological data on DILD has never been reported in a prospective manner. Method : From May 2002 to April 2004, total 487 patients with DILD were prospectively registered at Samsung Medical Center. The prospective observational analysis of the etiologies, its classification based on 2002 ATS/ERS (American Thoracic Society/European Respiratory Society) guidelines, as well as diagnostic tests and the retrospective analysis of the treatment modalities were carried out. Any infectious and malignant causes were excluded. Results : 1) The patients were classified into idiopathic interstitial pneumonia (IIP) in 269 patients (55.2%), known causes of DILD in 168 patients (34.5%), sarcoidosis in 27 patients (5.5%), other forms of DILD in 14 patients (2.9%), and undetermined DILD in 9 patients (1.9%). 2) The diagnostic test showed that most patients had undergone chest high resolution computed tomography (HRCT) and pulmonary function test (PFT) (97%, 89%). Transbronchial lung biopsy (TBLB) and surgical lung biopsy (SLB) were performed in limited patients (38%, 29%). 3) Among 269 patients with IIP, 220 (82%) had idiopathic pulmonary fibrosis (IPF) while 23 (9%) had nonspecific interstitial pneumonia. SLB was carried out in 36% of patients with IIP. 4) Symptomatic supportive care was given to 67% of IPF, but specific medical treatment including corticosteroids was administered to 89% of non-IPF patients. Conclusion : A nationwide registry of DILD patients is required to determine the annual incidence, etiology, and practice pattern of diagnosis and treatment in Korea.

Lack of evidence for a role of Epstein–Barr virus in the increase of lung cancer in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is known as an independent risk factor for lung cancer. Because Epstein–Barr virus (EBV) may be involved in the genesis of IPF as well as certain malignancies, we investigated whether EBV contributes to the increased incidence of lung cancer in IPF. The formalin-fixed and paraffin-embedded lung sections were prepared from 22 lung cancer patients with IPF and 22 lung cancer patients without IPF. All of the IPF patients pathologically showed usual interstitial pneumonia. In situ hybridization for EBV-encoded small non-polyadenylated RNAs failed to show positive signals in the cancer tissues of either IPF or non-IPF patients. This study did not provide evidence for an etiologic role of EBV in the development of lung cancer in IPF.

A clinical study of idiopathic pulmonary fibrosis based on autopsy studies in elderly patients.

The prevalence of idiopathic pulmonary fibrosis (IPF) tends to be greater in the elderly although the precise outcome is not known. The present study investigated the outcome of IPF in elderly patients whose pathological diagnosis corresponded to usual interstitial pneumonia (UIP) on autopsy findings. In a consecutive autopsy series, (n = 4,554 cases), complete information was obtained in 86 cases in which the clinical and pathological diagnosis was IPF and UIP, respectively. Mean subject age was 80.5 years and there were 52 males and 34 females. Median survival time (MST) was 3.5 years overall. Dyspnea ranking by the MRC dyspnea scale (DR) on admission was closely related to the outcome. When MST was compared between DR0 and DR1, or DR2 and DR3, the former patient group survived significantly longer than the latter (p < 0.05). Twenty percent of patients died of severe respiratory failure. Other causes of death were disease progression of IPF (10.5%), bacterial pneumonia (23.3%) and lung cancer (17.4%). The patients in the young-elderly group (age < 75) survived for a significantly longer period than those in the old-elderly group (age > or = 75) (MST; 5.5 vs 2.0 years; p < 0.001). Both lung cancer and pneumonia were significantly more prevalent among IPF patients than among non-IPF patients; these IPF with lung cancer profoundly reflected the smoking history of IPF patients. The poor outcome in IPF in elderly patients was characterized by more severe dyspnea, advanced age and co-morbidity.

Clinicopathological characteristics of surgically resected lung cancer associated with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lung cancer. It is important to clarify the clinical and pathological features of lung cancer with IPF in understanding the pathogenesis of lung cancer in IPF patients. We compared clinicopathological factors of lung cancer in patients with and without IPF. A retrospective study was conducted in 711 surgically resected lung cancer patients. Medical records were compared of IPF and non-IPF patients. Of the 711 patients, 53 (7.5%) were IPF patients. Lung cancer in IPF patients was more frequent in elderly male smokers. Most lung cancers in IPF (79%) arose in peripheral areas involving fibrosis (P < 0.01). The incidence of squamous cell carcinoma in the IPF patients (46%) was significantly higher than that in non-IPF patients (22%) (P < 0.01). The incidence of multiple lung cancer in IPF cases (17%) was also significantly higher. These results suggest that IPF has the potential to develop into lung cancer, especially peripheral squamous cell carcinoma. Further molecular analyses are necessary to clarify the relationship between IPF and lung cancer.

Fluorescein iridography.

<b>Background:</b> Interstitial lung diseases (ILD) are a heterogenous group of mainly chronic lung diseases. For idiopathic pulmonary fibrosis (IPF) a high burden of disease was recently shown. The development of health-related quality of life (HRQL) of IPF patients compared to other ILD subtypes is sparsely investigated. <b>Methods:</b> We measured generic HRQL (Visual Analog Scale (VAS)) and disease-specific HRQL (King’s Brief Interstitial Lung Disease questionnaire (K-BILD) and its domains breathlessness and activities, chest symptoms, psychological impact)) for 164 ILD patients at baseline and after 12 months. Important change were operationalized via minimally important difference (MID). Next, we adjusted HRQL change for sociodemographic variables and for FVC % predicted, baseline HRQL, and comorbidity burden. <b>Results:</b> 25.0% of patients had IPF, 69.5% were male, median age was 66.5, baseline ØFVC % pred was 74.9 (SD:21.1) and Ø DLCO % pred was 44.8 (SD:16.5). 24.4% IPF vs 13.8% non-IPF patients deteriorated on K-BILD more than MID, and 39.0% vs 22% on VAS. 4.9% vs 14.6% improved on K-BILD, and 26.8% vs 22.0 % on VAS more than MID. Mean change in VAS (-3.1) was same in both groups, but K-BILD change was bigger for IPF (-3.0 vs. -0.2). Change in breathlessness domain differed significantly between IPF (-7.8) and non-IPF (-0.2), but change in the chest domain (-9.0 vs -2.8), and psychological impact (-1.47 vs 0.05) did not. There were no group differences in the adjusted model. <b>Discussion:</b> HRQL deteriorates over time in all ILD patients. IPF patients show a faster decline, especially for breathlessness; yet differences disappear after adjustments. Thus worsening of HRQL might be underestimated in ILD in general.