Stages Of Idiopathic Pulmonary Fibrosis Research Articles

An observational cohort study of interstitial lung abnormalities (ILAs) in a large Japanese health screening population (Kumamoto ILA study in Japan: KILA-J)

BackgroundInterstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5% of the lungs on computed tomography (CT) scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment.MethodsThis is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70,000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression, including quantitative assessment by artificial intelligence.DiscussionThis is the first prospective, multicentre, observational study to clarify (i) the aetiological data of patients with ILA from the largest general health check-up population, (ii) the natural course of IPF or PPF from the asymptomatic stage, and (iii) the effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. The results of this study could significantly impact the clinical practice and treatment strategy for progressive fibrosing interstitial lung diseases.Trial registration numberUMIN000045149.

Characteristics of idiopathic pulmonary fibrosis -associated cough. a case-control study

BackgroundMost patients with idiopathic pulmonary fibrosis (IPF) complain of cough. IPF-associated cough is widely characterized as dry or non-productive. The aim of this study was to compare chronic cough in early stage IPF patients to cough in subjects with chronic cough from a community-based sample and, especially, to investigate whether cough in IPF is less productive than chronic cough in a community-based sample.MethodsThe IPF cough population consisted of 46 biopsy-confirmed patients who complained of chronic cough. Control population consisted of subjects with chronic cough, gathered by a community-based email survey sent to public service employees and the Finnish Pensioners’ Federation. A case-control setting was applied by having four age, gender, and smoking-status matched subjects from the community sample for each IPF cough patient. A cough specific quality of life questionnaire (Leicester Cough Questionnaire (LCQ)) was filled in by all subjects. The LCQ questionnaire contains 19 questions, each question is scored from 1 to 7 and total score from 3 to 21 with a smaller value indicating more severe impairment.ResultsThe sputum production frequency, as assessed by LCQ question 2, was 5.0 (3.0-6.0) in the IPF chronic cough population and 5.0 (3.0–6.0) in the community-based chronic cough population (median and interquartile range p= 0.72). The LCQ total score was 14.8 (11.5-18.1) in the IPF chronic cough population and 15.4 (13.0–17.5) in the community-based chronic cough population (p=0.76). The domain impact scores were physical, 4.9 (3.9–6.1) vs. 5.1 (4.5–5.6) (p=0.80); psychological, 4.6 (3.7–5.9) vs. 4.7 (3.9–5.7) (p=0.90); and social, 5.5 (3.7–6.5) vs. 5.5 (4.5–6.3) (p=0.84), respectively. Furthermore, cough response to paint or fumes, cough disturbing sleep, and cough frequency per day did not differ between the groups.ConclusionCough in early stage IPF patients was not distinguishable from chronic cough in the community-based population by LCQ. Especially, there was no difference in the self-reported frequency of cough-associated sputum production.

Evaluation of an ex vivo fibrogenesis model using human lung slices prepared from small tissues

BackgroundIn recent years, there have been breakthroughs in the preclinical research of respiratory diseases, such as organoids and organ tissue chip models, but they still cannot provide insight into human respiratory diseases well. Human lung slices model provides a promising in vitro model for the study of respiratory diseases because of its preservation of lung structure and major cell types.MethodsHuman lung slices were manually prepared from small pieces of lung tissues obtained from lung cancer patients subjected to lung surgery. To evaluate the suitability of this model for lung fibrosis research, lung slices were treated with CdCl2 (30 μM), TGF-β1 (1 ng/ml) or CdCl2 plus TGF-β1 for 3 days followed by toxicity assessment, gene expression analysis and histopathological observations.ResultsCdCl2 treatment resulted in a concentration-dependent toxicity profile evidenced by MTT assay as well as histopathological observations. In comparison with the untreated group, CdCl2 and TGF-β1 significantly induces MMP2 and MMP9 gene expression but not MMP1. Interestingly, CdCl2 plus TGF-β1 significantly induces the expression of MMP1 but not MMP2, MMP7 or MMP9. Microscopic observations reveal the pathogenesis of interstitial lung fibrosis in the lung slices of all groups; however, CdCl2 plus TGF-β1 treatment leads to a greater alveolar septa thickness and the formation of fibroblast foci-like pathological features. The lung slice model is in short of blood supply and the inflammatory/immune-responses are considered minimal.ConclusionsThe results are in favor of the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated by tissue damage and abnormal repair. Induction of MMP1 gene expression and fibroblast foci-like pathogenesis suggest that this model might represent an early stage of IPF.

Evaluating the Effect of Hydrogen Sulfide in the Idiopathic Pulmonary Fibrosis Model with a Fluorescent Probe.

Hydrogen sulfide (H2S), a gaseous signaling molecule, is involved in a wide range of physiological and pathological processes. H2S has been proven to play a beneficial role in lung diseases, and the relationship between perturbations in endogenous H2S synthesis and degree with idiopathic pulmonary fibrosis (IPF) has attacted increasing attention. However, the changes in endogenous lung H2S levels in the pathological progression of chronic pulmonary diseases remain unclear. To this end, we synthesized a fluorescent probe (Bcy-HS) for the selective imaging of H2S in living cells and mice. This probe was mainly used for in situ in vivo and cellular imaging as well as a systematic assessment of intrapulmonary H2S levels at different stages of IPF. In addition, we also discussed the potential of H2S supplementation in the treatment of pulmonary fibrotic diseases. Our results confirmed the key role of H2S in pulmonary fibrosis. In cellular and mice models of pulmonary fibrosis, intracellular H2S levels are reduced. However, the severity of oxidative damage and pulmonary fibrosis decreased after NaSH (H2S donor). Therefore, we concluded that increasing the H2S content in vivo may be a novel strategy for IPF treatment.

The clinical efficacy of a mixture of ivy leaf extract and coptidis rhizome in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis and cough is the one of most common and major symptoms in IPF. The aim of this study was to evaluate the clinical efficacy of a Mixture of Ivy Leaf Extract and Coptidis rhizome (Synatura®) in patients with IPF. This was a prospective, open-label, single-center, and single-arm study in Korea from October 2019 to September 2020. IPF patients with chronic bronchitis were enrolled. Between baseline and eight weeks after use of Synatura®, clinical measures regarding cough and health-related quality of life, and the systemic inflammatory markers was prospectively collected. Thirty patients were enrolled. Median age was 73 years and 86.7% were men. The median gender-age-pulmonary function stage of IPF was 3. Baseline total score of Leicester cough questionnaire (LCQ) and St. George respiratory questionnaire (SGRQ) were 104.5 and 30.59 respectively. After eight weeks, there was no significant improvement in LCQ (16.8 [15.6-19.1] vs 17.5 [15.2-18.9], P = .772) and SGRQ (30.6 [19.4-37.8] vs 29.9 [19.6-41.8], P = .194) scores. Also, there was no significant difference of systemic inflammatory markers. In analysis of minimal clinically important differences (MCID), one third (33.3%) patients fulfilled the criteria of MCID (1.3) in LCQ scores and median differences was 14 (range: 10-18). In terms of SGRQ, 6 patients (20%) reached MCID (4.0) without significant predictive factors. In our study, use of Synatura® during 8 weeks improved cough-specific life quality in one third patients with IPF. Large-scale, randomized, double-blind, and placebo-controlled clinical trials are needed.

THE TALE OF THE TRAVELING CHEESE: SHIGELLA IN A LUNG TRANSPLANT PATIENT

TOPIC: Transplantation TYPE: Fellow Case Reports INTRODUCTION: Shigella is a common cause of gastroenteritis in areas of overcrowding and poor sanitation, but is seen less frequently in the developed world. Infection is mainly acquired through the fecal-oral route, but consumption of unpasteurized dairy remains a high risk for transmission. In this report, we describe a case of a lung transplant patient who presented with septic shock secondary to Shigella gastroenteritis after ingesting unpasteurized cheese brought back from Peru. CASE PRESENTATION: This is a case of a 62-year-old Peruvian man who underwent a bilateral lung transplant for end stage idiopathic pulmonary fibrosis in November 2018, a year prior to this presentation. Pre-transplant the patient status was CMV +/+, EBV +/+. At time of presentation his immunosuppression regimen consisted of Tacrolimus 0.5 mg, Mycophenolate 500mg twice daily and Prednisone 10mg daily.He had been progressing well until he presented to the emergency department with a reported fever of 103 degrees Fahrenheit, around 40 episodes a day of profuse non-bloody, watery diarrhea and abdominal discomfort. He did not complain of nausea or vomiting. He revealed that he had eaten soft, white, unpasteurized cheese that was brought from Peru two days prior.He was hypotensive with a blood pressure of 72/39, a heart rate of 107 beats per minute and SaO2 of 96% while breathing ambient air. A physical exam revealed mild diffuse abdominal tenderness, rest of exam was normal.Laboratory examination revealed a white blood cell count of 18,000 cells/mcl, platelet (PLT) count of 147,000 cells/mcl, creatinine 1.30 mg/dL, lactic acid 3.2 mmol/L. Computerized tomography (CT) of his abdomen showed fluid filled loops of the colon and small bowel, reflecting enteritis and diarrhea. Stool studies were sent. The patient was treated with intravenous fluids, Tacrolimus was held due to new acute kidney injury, Mycophenolate held due to leukopenia and Cefepime and Metronidazole were administered for empiric coverage for abdominal pathogens. On day 4 of admission Shigella flexneri (sensitive to Levofloxacin and Ceftriaxone, resistant to Ampicillin) was isolated and infectious disease consultation obtained. The patient had clinically recovered on Cefepime and he completed the antibiotic course. He was discharged the following day on his routine triple immunosuppressive therapy. DISCUSSION: Solid organ transplant recipients with diarrhea should be tested for shigella. Patients not responding to conventional treatment should undergo repeat culture and sensitivity testing. Bacterial culture is the gold standard for diagnosis of shigella infections. The use of antibiotics depends on the severity of illness, the age of the patient and immune status. CONCLUSIONS: This case highlights the importance of educating transplant patients on how to reduce certain harmful exposures that may be fatal in immunosuppressed individuals. REFERENCE #1: 1. GBD 2016 Diarrhoeal Disease Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 2018. REFERENCE #2: 2. Kotloff KL, Winickoff JP, Ivanoff B, et al. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull World Health Organ 1999; 77:651–66 REFERENCE #3: 3. Livio S, Strockbine NA, Panchalingam S, et al. Shigella isolates from the global enteric multicenter study inform vaccine development. Clin Infect Dis 2014; 59: 933–41. DISCLOSURES: No relevant relationships by Nikhil Madan, source=Web Response No relevant relationships by Vipul Patel, source=Web Response No relevant relationships by Safiyya Quintiliani, source=Web Response

Novel Artificial Intelligence-based Technology for Chest Computed Tomography Analysis of Idiopathic Pulmonary Fibrosis.

Rationale: There is a growing need to accurately estimate the prognosis of idiopathic pulmonary fibrosis (IPF) in clinical practice, given the development of effective drugs for treating IPF. Objectives: To develop artificial intelligence-based image analysis software to detect parenchymal and airway abnormalities on computed tomographic (CT) imaging of the chest and to explore their prognostic importance in patients with IPF. Methods: A novel artificial intelligence-based quantitative CT image analysis software (AIQCT) was developed by applying 304 high-resolution CT (HRCT) scans from patients with diffuse lung diseases as the training set. AIQCT automatically categorized and quantified 10 types of parenchymal patterns as well as airways, expressing the volumes as percentages of the total lung volume. To validate the software, the area percentages of each lesion quantified by AIQCT were compared with those of the visual scores using 30 plain high-resolution CT images with lung diseases. In addition, three-dimensional analysis for similarity with ground truth was performed using HRCT images from 10 patients with IPF. AIQCT was then applied to 120 patients with IPF who underwent HRCT scanning of the chest at our institute. Associations between the measured volumes and survival were analyzed. Results: The correlations between AIQCT and the visual scores were moderate to strong (correlation coefficient 0.44-0.95) depending on the parenchymal pattern. The Dice indices for similarity between AIQCT data and ground truth were 0.67, 0.76, and 0.64 for reticulation, honeycombing, and bronchi, respectively. During a median follow-up period of 2,184 days, 66 patients died, and 1 underwent lung transplantation. In multivariable Cox regression analysis, bronchial volumes (adjusted hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.16-1.53) and normal lung volumes (adjusted HR, 0.97; 95% CI, 0.94-0.99) were independently associated with survival after adjusting for the gender-age-lung physiology stage of IPF. Conclusions: Our newly developed artificial intelligence-based image analysis software successfully quantified parenchymal lesions and airway volumes. Bronchial and normal lung volumes on HRCT imaging of the chest may provide additional prognostic information on the gender-age-lung physiology stage of IPF.

Inhibition of the SET8 Pathway Ameliorates Lung Fibrosis Even Through Fibroblast Dedifferentiation.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown etiopathogenesis. The activation of extracellular matrix (ECM)-producing myofibroblasts plays a key role in fibrotic tissue remodeling. The dedifferentiation of myofibroblasts has attracted considerable attention as a promising target for the development of effective therapeutic interventions against IPF. Here, we screened a small library of epigenetics-related inhibitors using dedifferentiation assay of lung myofibroblasts prepared from a patient at the terminal stages of IPF and chose UNC0379. The inhibition of SET8, a histone H4 lysine 20 (H4K20) monomethyltransferase, by UNC0379 markedly suppressed the expression of α-smooth muscle actin (SMA) and ED-A-fibronectin in myofibroblasts. In IPF myofibroblasts, SET8 expression and H4K20 monomethylation (H4K20me1) levels, which were significantly higher than those in normal human lung fibroblasts, were reduced upon treatment with UNC0379. Hence, the changes in the expression of the two fibrotic markers clearly correlated with those in SET8 expression and H4K20me1 level. Furthermore, in a mouse model of bleomycin (BLM)-induced lung fibrosis, the intratracheal administration of UNC0379 at an early fibrotic stage markedly ameliorated the histopathological changes associated with collagen deposition in the lungs. However, treatment with UNC0379 did not significantly affect the number of proinflammatory cells or cytokine production in the bronchoalveolar lavage fluids from mice treated with BLM. In the BLM-injured lung, SET8 was predominantly localized to the nuclei of α-SMA-positive cells, which colocalized with H4K20me1. Taken together, our results indicate that the inhibition of SET8 resulting in myofibroblast dedifferentiation may partly mitigate lung fibrosis without affecting the inflammatory responses.

A modified GAP model for East-Asian populations with idiopathic pulmonary fibrosis.

The easy-to-calculate gender, age, and lung physiology (GAP) model shows good predictive and discriminative performance in the prognosis of idiopathic pulmonary fibrosis (IPF). However, the GAP model was not effective in predicting the prognosis accurately in previous Japanese and Korean IPF cohort studies. Therefore, we developed a modified GAP model for the East-Asian populations by weighing the GAP variables. The validity of the modified GAP model was subsequently evaluated in East-Asian IPF patients. The derivation cohort comprised 326 patients with IPF. Weights of the variables were adjusted on the basis of coefficients derived from Cox regression models. The total points were distributed to the three stages of the disease so that the number of patients included in each stage was appropriate. The validity of the modified model was analyzed in another Japanese cohort of 117 patients with IPF and a nationwide cohort of Korean patients with IPF. Predicted survival rates differed significantly in the derivation cohort using the modified GAP model for each stage of IPF (log-rank test: stage I vs. stage II, p<0.001; stage II vs. stage III, p<0.001). Model performance improved according to Harrell's C-index (at three years: 0.696 in the original GAP model to 0.738 in the modified model). The performance of the modified model was validated in the Japanese validation and Korean national cohorts. Our modification of the original GAP model showed improved performance in East-Asian IPF patient populations.

Treatment of acute lung injury and early- and late-stage pulmonary fibrosis with combination emulsion siRNA polyplexes

Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are severe lung diseases causing irreversible lung damage and premature death. Both diseases share multiple pathological features, including overexpression of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of plasminogen activator inhibitor-1 (PAI-1). The goal of the present study was to evaluate therapeutic potential of pulmonary treatment with combined inhibition of CXCR4 and PAI-1 in ALI and various disease stages of IPF. We report preparation of perfluorocarbon emulsion polyplexes containing a fluorinated polymeric CXCR4 antagonist (F-PAMD) as an siRNA carrier suitable for pulmonary delivery. In vitro testing of the emulsion polyplexes in primary lung fibroblasts from IPF mice showed high cellular uptake and promising antifibrotic effect as indicated by the decreased expression of α smooth muscle actin, when compared with conventional siRNA polyplexes. Biodistribution analysis in mice with IPF showed prolonged lung retention and widespread lung distribution following intratracheal administration of the formulations. The emulsion polyplexes showed promising therapeutic efficacy in ALI and in early fibrinogenic stage of IPF. Increased survival was observed in the model of late-stage IPF. The use of perfluorocarbon emulsion polyplexes to achieve combined CXCR4 antagonism and PAI-1 inhibition is a promising strategy for treatment of ALI and IPF.

Interstitial lung abnormalities and physical function.

Reductions in objectively measured physical function are associated with interstitial lung abnormalities http://ow.ly/azAW30kMhqv

A Volumetric Computed Tomography Analysis of the Normal Lung in Idiopathic Pulmonary Fibrosis: The Relationship with the Survival.

Objective An image analysis of high-resolution computed tomography (HRCT) can provide objective quantitation of the disease status in idiopathic pulmonary fibrosis (IPF). However, to our knowledge, no reports have investigated the utility of the normal lung volume for evaluating mortality from IPF. This study aimed to evaluate the relationship between the normally attenuated lung volume on HRCT as a percentage of whole-lung volume (NL%) and IPF mortality. Methods The NL% was determined by HRCT (between -950 and -701 Hounsfield units) using a density mask technique and volumetric software. The NL%, visual assessments of the normal lung by two radiologists, pulmonary function variables, and the gender, age, and physiology (GAP) index were retrospectively evaluated for 175 patients with IPF. Uni- and multivariate Cox proportional hazards analyses and C statistics for mortality were performed. Results The univariate Cox proportional hazards analysis identified the NL% as a prognostic factor [hazard ratio, 0.949; 95% confidence interval (CI), 0.936-0.964; p<0.0001]. In the multivariate analysis, the NL% was a prognostic factor, but the radiologists' visual assessment scores of normal lung were not. The C index increased when the NL% was included in the models of the pulmonary function variables. Furthermore, the C index for a combined model of GAP stage and categorized NL% (0.758; 95% CI, 0.751-0.762) was higher than for the model with the GAP stage alone (0.689; 95% CI, 0.672-0.709). Conclusion The NL% was a prognostic factor in our study population. Quantification of the normal lung using our method may help improve the IPF staging systems.

Drug repurposing in idiopathic pulmonary fibrosis filtered by a bioinformatics-derived composite score

Idiopathic Pulmonary Fibrosis (IPF) is a rare disease of the respiratory system in which the lungs stiffen and get scarred, resulting in breathing weakness and eventually leading to death. Drug repurposing is a process that provides evidence for existing drugs that may also be effective in different diseases. In this study, we present a computational pipeline having as input a number of gene expression datasets from early and advanced stages of IPF and as output lists of repurposed drugs ranked with a novel composite score. We have devised and used a scoring formula in order to rank the repurposed drugs, consolidating the standard repurposing score with structural, functional and side effects’ scores for each drug per stage of IPF. The whole pipeline involves the selection of proper gene expression datasets, data preprocessing and statistical analysis, selection of the most important genes related to the disease, analysis of biological pathways, investigation of related molecular mechanisms, identification of fibrosis-related microRNAs, drug repurposing, structural and literature-based analysis of the repurposed drugs.

Staging of idiopathic pulmonary fibrosis

Staging of idiopathic pulmonary fibrosis

Pathway‑based detection of idiopathic pulmonary fibrosis at an early stage.

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial pneumonia and the most aggressive interstitial lung disease. Usually, IPF is confirmed by the histopathological pattern of typical interstitial pneumonia and requires an integrated multidisciplinary approach from pulmonologists, radiologists and pathologists. However, these diagnoses are performed at an advanced stage of IPF. At present, pathway-based detection requires investigation, as it can be performed at an early stage of the disease. The aim of the present study was to find an effective method of diagnosing IPF at an early stage. Microarray data for E-GEOD-33566 were downloaded from the ArrayExpress database. Human pathways were downloaded from Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. An individual pathway-based method to diagnose IPF at an early stage was introduced. Pathway statistics were analyzed with an individualized pathway aberrance score. P-values were obtained with different methods, including the Wilcoxon test, linear models for microarray data (Limma) test and attract methods, generating three pathway groups. Support vector machines (SVM) were used to identify the best group for diagnosing IPF at an early stage. There were 106 differential pathways in Wilcoxon-based KEGG Pathway (n>5) group, 100 in the Limma-based KEGG Pathway (n>5) group, and seven in the attract-based KEGG Pathway (n>5) group. The pathway statistics of these differential pathways in three groups were analyzed with linear SVM. The results demonstrated that the Wilcoxon-based KEGG Pathway (n>5) group performed best in diagnosing IPF.

Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial–mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow-derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial–mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 μm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-β signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-β signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF.

NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.

The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an age-related multifactorial disease featuring non-uniform lung fibrosis. The decisive cellular events at early stages of IPF are poorly understood. While the involvement of club cells in IPF pathogenesis is unclear, their migration has been associated with lung fibrosis. In this study, we labeled club cells immunohistochemically in IPF lungs using a club cell marker Claudin-10 (Cldn10), a unique protein based on the recent report which demonstrated that the appearance of Cldn10 in developing and repairing lungs precedes other club cell markers including club cell secretory protein (CCSP). Cldn10-positive cells in IPF lungs displayed marked pleomorphism and were found in varied arrangements, suggesting their phenoconversion. These results were corroborated by immunogold labeling for Cldn10. Further, immunohistochemical double-labeling for Cldn10 and α-smooth muscle actin (α-SMA) demonstrated that aberrant α-SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium of IPF lungs. Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities. Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF.

Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis.

BackgroundAlthough several computer-aided computed tomography (CT) analysis methods have been reported to objectively assess the disease severity and progression of idiopathic pulmonary fibrosis (IPF), it is unclear which method is most practical. A universal severity classification system has not yet been adopted for IPF.ObjectiveThe purpose of this study was to test the correlation between quantitative-CT indices and lung physiology variables and to determine the ability of such indices to predict disease severity in IPF.MethodsA total of 27 IPF patients showing radiological UIP pattern on high-resolution (HR) CT were retrospectively enrolled. Staging of IPF was performed according to two classification systems: the Japanese and GAP (gender, age, and physiology) staging systems. CT images were assessed using a commercially available CT imaging analysis workstation, and the whole-lung mean CT value (MCT), the normally attenuated lung volume as defined from −950 HU to −701 Hounsfield unit (NL), the volume of the whole lung (WL), and the percentage of NL to WL (NL%), were calculated.ResultsCT indices (MCT, WL, and NL) closely correlated with lung physiology variables. Among them, NL strongly correlated with forced vital capacity (FVC) (r = 0.92, P <0.0001). NL% showed a large area under the receiver operating characteristic curve for detecting patients in the moderate or advanced stages of IPF. Multivariable logistic regression analyses showed that NL% is significantly more useful than the percentages of predicted FVC and predicted diffusing capacity of the lungs for carbon monoxide (Japanese stage II/III/IV [odds ratio, 0.73; 95% confidence intervals (CI), 0.48 to 0.92; P < 0.01]; III/IV [odds ratio. 0.80; 95% CI 0.59 to 0.96; P < 0.01]; GAP stage II/III [odds ratio, 0.79; 95% CI, 0.56 to 0.97; P < 0.05]).ConclusionThe measurement of NL% by threshold-based volumetric CT analysis may help improve IPF staging.

Staging of idiopathic pulmonary fibrosis: past, present and future.

Idiopathic pulmonary fibrosis (IPF) is traditionally staged with terms such as "mild", "severe", "early" and "advanced" based on pulmonary function tests. This approach allows physicians to monitor disease progression and advise patients and their families. However, it is not known if the stages of this model reflect distinct biological or clinical phenotypes and the therapeutic and prognostic value of this system is limited. Novel methods of IPF staging have recently been developed. The GAP model includes four baseline variables that were found to be predictive of outcome, as identified by logistic regression. These factors are: gender (G), age (A) and two lung physiology variables (P) (forced vital capacity and diffusing capacity of the lung for carbon monoxide). The clinical utility and accuracy of staging models may be further improved in the future by the integration of dynamic parameters that can be measured over time, as well as biological data from biomarkers which may be able to directly measure disease activity. The development of an evidence-based, multidimensional IPF staging model that builds on the current staging approaches to IPF is an important objective for improving the management of IPF.