Ulla Hodgson

ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses

Viral infections and abnormal host response are thought to cause epithelial injury in idiopathic pulmonary fibrosis (IPF). To understand IPF pathogenesis, we have used overexpression cell models and expression microarrays to discover genes networked with ELMO domain containing 2 (ELMOD2) gene genetically implicated in IPF. The identified pathways were confirmed in vitro, and ELMOD2 protein expression was characterized in tissue samples. Here 303 genes were significantly altered after ELMOD2 transfec‐tion of human alveolar epithelial A549 cell line. The enriched pathways were interferon induction, viral response, antigen processing and presentation, and I‐/ nuclear factor‐κΒ signaling. ELMOD2 showed immunoreactivity in macrophages and type II alveolar epithelial cells in normal human lung. In A549 cells, forced expression of ELMOD2 increased type I and type III interferon mRNA expression, and ELMOD2specific siRNA molecules inhibited expression of these antiviral cytokines in response to Toll‐like receptor three (TLR3) activation. In human macrophages silencing of ELMOD2 inhibited TLR3‐dependent expression of type I and type III interferon genes. Influenza A virus infection decreased ELMOD2 mRNA expression in A549 cells and macrophages suggesting negative regulation in viral infections. In summary, our results show that TLR3 pathway is dependent on ELMOD2.—Pulkkinen, V., Bruce, S., Rintahaka, J., Hodgson, U., Laitinen, T., Alenius, H., Kinnula, V. L., Myllarniemi, M., Matikainen, S., Kere, J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB J. 24, 1167–1177 (2010). www.fasebj.org

Idiopathic pulmonary fibrosis - a systematic review on methodology for the collection of epidemiological data

BackgroundRecent studies suggest that the incidence of idiopathic pulmonary fibrosis (IPF) is rising. Accurate epidemiological data on IPF, however, are sparse and the results of previous studies are contradictory. This study was undertaken to gain insight into the various methods used in the epidemiological research of IPF, and to get accurate and comparable data on these different methodologies.MethodsA systematic database search was performed in order to identify all epidemiological studies on IPF after the previous guidelines for diagnosis and treatment were published in 2000. Medline (via Pubmed), Science Sitation Index (via Web of Science) and Embase databases were searched for original epidemiological articles published in English in international peer-reviewed journals starting from 2001. After pre-screening and a full-text review, 13 articles were accepted for data abstraction.ResultsThree different methodologies of epidemiological studies were most commonly used, namely: 1) national registry databases, 2) questionnaire-based studies, and 3) analysis of the health care system’s own registry databases. The overall prevalence and incidence of IPF varied in these studies between 0.5–27.9/100,000 and 0.22–8.8/100,000, respectively. According to four studies the mortality and incidence of IPF are rising.ConclusionsWe conclude that there are numerous ways to execute epidemiological research in the field of IPF. This review offers the possibility to compare the different methodologies that have been used, and this information could form a basis for future studies investigating the prevalence and incidence of IPF.

A novel screening method detects herpesviral DNA in the idiopathic pulmonary fibrosis lung

Abstract Background. Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF). Methods. We identified herpesviral DNA from IPF and control lung tissue using a multiplex PCR-and microarray-based method. Active herpesviral infection was detected by standard methods, and inflammatory cell subtypes were identified with specific antibodies. Patients that underwent lung transplantation were monitored for signs of herpesviral infection. Results. A total of 11/12 IPF samples were positive for Epstein-Barr virus (EBV) and 10/12 for human herpesvirus 6B (HHV-6B) DNA. Control lung samples (n = 10) were negative for EBV DNA, whereas three samples were positive for HHV-6B. EBV-encoded RNA (EBER) was identified in nine IPF samples and localized mainly to lymphocytic aggregates. HHV-6B antigens were detected in mononuclear cells in IPF lung tissue. CD20+ B lymphocytic aggregates that were surrounded by CD3+ T cells were abundant in IPF lungs. CD23+ cells (activated B cells, EBV-transformed lymphoblasts, and dendritic cells) were observed in the aggregates. IPF patients had no signs of increased herpesviral activation after lung transplantation. Conclusions. Inflammatory cells are the main source of herpesviral DNA in the human IPF lung. Diagnostic tools should be actively used to elucidate whether herpesviral infection affects the pathogenesis, progression, and/or exacerbation of IPF.

Are physicians in primary health care able to recognize pulmonary fibrosis

ABSTRACT Background: The early diagnosis of idiopathic pulmonary fibrosis (IPF) has become increasingly important due to evolving treatment options. IPF patients experience a significant delay in receiving an accurate diagnosis, thus delayed access to tertiary care is associated with higher mortality independently from disease severity. Objective: The aims were to evaluate whether there had been a delay in the referral process, and to determine whether the referring doctors had suspected IPF or other interstitial lung disease (ILD) already during the time of referral. Methods: Ninety-five referral letters of patients with IPF identified from the FinnishIPF registry were evaluated with respect to time of referral, referring unit, grounds for referral, symptoms, smoking status, occupational history, clinical examinations, co-morbidities, medication, radiological findings and lung function. Results: Fifty-nine percent of referral letters originated from primary public health care. The time from symptom onset to referral was reported in 60% of cases, mean time being 1.5 (0.8–2.3) (95%CI) years. The main reason for referral was a suspicion of interstitial lung disease (ILD) (63%); changes in chest X-ray were one reason for referring in 53% of cases. Lung auscultation was reported in 70% and inspiratory crackles in 52% of referral letters. Conclusions: Primary care doctors suspected lung fibrosis early in the course of disease. Lung auscultation and chest X-rays were the most common investigational abnormalities in the referrals. Providing general practitioners with more information of ILDs might shorten the delay from symptom onset to referral.

Work of Breathing in Obesity Assessed with Body Plethysmography Comparison with Emphysematic COPD and Pulmonary Fibrosis

Objectives: Body plethysmography is a lung function testing method usually applied for determination of thoracic gas volume and airways resistance, but option to measure work of breathing is available in most models. Although the method has been known over fifty years, assessment of work of breathing with it has not yet systematically studied in obesity. The aim of the study was to evaluate the relevance of work of breathing measured by body plethysmography in obese subjects and to compare the results with those of healthy controls and patients with pulmonary diseases of different pulmonary mechanics. Methods: Altogether sixty-two adults were studied prospectively: healthy non-smoking obese subjects (BMI > 30, N = 15), patients with interstitial lung disease (ILD) (N =15), emphysematic COPD (emphysema) (N = 16) and healthy non-smoking controls (controls) (N = 16). Inspiratory, expiratory and total work of breathing (WOBin, WOBex and WOB) and specific work of breathing (sWOBin, sWOBex and sWOB) were measured. Results: In obese subjects, WOB, WOBin (p < 0.001) and WOBex (p = 0.002) were elevated in comparison to controls. Also in ILD, WOB was significantly higher than in controls (p < 0.006). sWOBin, sWOBex and SWOB were significantly higher in emphysema than in the controls (p < 0.001). Conclusions: In obesity and ILD WOB whereas in emphysematic COPD sWOB differed significantly from controls, which is caused by differences in lung mechanics and lung volumes. The results concerning COPD correspond earlier study, but the present results suggest that body plethysmography is suitable for the assessment of work of breathing also in obesity.

Thoracic gas compression during forced expiration in patients with emphysema, interstitial lung disease and obesity

BackgroundDynamic gas compression during forced expiration has an influence on conventional flow-volume spirometry results. The extent of gas compression in different pulmonary disorders remains obscure. Utilizing a flow plethysmograph we determined the difference between thoracic and mouth flows during forced expiration as an indication of thoracic gas compression in subjects with different pulmonary diseases characterized by limitations in pulmonary mechanics.MethodsPatients with emphysema (N = 16), interstitial lung disease (ILD) (N = 15), obesity (N = 15) and healthy controls (N = 16) were included. Compressed expiratory flow-volume curves (at mouth) and corresponding compression-free curves (thoracic) were recorded. Peak flow (PEF) and maximal flows at 75%, 50% and 25% of remaining forced vital capacity (MEF75, MEF50 and MEF25) were derived from both recordings. Their respective difference was assessed as an indicator of gas compression.ResultsIn all groups, significant differences between thoracic and mouth flows were found at MEF50 (p < 0.01). In controls, a significant difference was also measured at MEF75 (p <0.005), in emphysema subjects, at PEF and MEF75 (p < 0.05, p < 0.005) and in obese subjects at MEF75 (p <0.005) and MEF25 (p < 0.01). ILD patients showed the lowest difference between thoracic and mouth flows at MEF75 relative to controls and emphysema patients (p < 0.005, p < 0.001). Obese subjects did not differ from controls, however, the difference between thoracic and mouth flows was significantly higher than in patients with emphysema at MEF50 (p < 0.001) and MEF25 (p < 0.005).ConclusionsAlveolar gas compression distorts the forced expiratory flow volume curve in all studied groups at the middle fraction of forced expiratory flow. Consequently, mouth flows are underestimated and the reduction of flow measured at 75% and 50% of vital capacity is often considerable. However, gas compression profiles in stiff lungs, in patients with decreased elastic recoil in emphysema and in obesity differ; the difference between thoracic and mouth flows in forced expiration was minimal in ILD at the first part of forced expiration and was higher in obesity than in emphysema at the middle and last parts of forced expiration.