University of Helsinki - Pulmonary Research Group

Research subject
Chronic airway diseases and parenchymal lung disorders: From genetics and proteomics to diagnostic approaches

Group leaders
Ville Pulkkinen, PhD
Adjunct professor, Principal Investigator
Department of Medicine, Pulmonary division
University of Helsinki
Finland
ville.pulkkinen (at) helsinki.fi

Witold Mazur, MD PhD
Adjunct professor, Specialist in Respiratory Medicine
Department of Medicine, Pulmonary division
Helsinki University Central Hospital
Finland
witold.mazur (at) helsinki.fi

Research
The research group continues the work of the late Professor Vuokko Kinnula (1947-2012). Our major interest is on early assessment of different chronic airway and parenchymal lung diseases. Our research relies on identification of novel biomarkers by high-throughput proteomics and next-generation sequencing methods that have the potential for subphenotyping of patients in relation to clinical outcome or responsiveness to treatment.

Chronic Airway Disease (CAD) consists of a group of different phenotypes with overlapping features, variable airway obstruction, and destruction of the lung parenchyma (emphysema and fibrosis). The diagnosis of these disorders is mainly based on lung function tests, such as spirometry. The diagnosis of asthma is based on reversible airway obstruction and the diagnosis of chronic obstructive pulmonary disease (COPD) on virtually irreversible obstruction. The diagnosis of most parenchymal lung diseases finally relies on lung biopsy.

COPD is an underdiagnosed disease suggested to be the 3rd - 4th most common disease causing mortality and morbidity by 2020. Globally COPD is not only associated with smoking but also with exposure to pollution and biomass fumes. COPD is a complex syndrome with a very heterogeneous clinical presentation. Within what is known as COPD, different phenotypes can be defined that have clinical, prognostic and therapeutic repercussions.

Although asthma and COPD represent two distinct diseases with different pathogenesis and risk factors, they share certain clinical characteristics that may overlap in adult patients. Common nominators behind COPD include persistent systemic inflammation, oxidant/antioxidant and protease/antiprotease imbalance. So far no reliable and validated biomarker (sputum or blood) has emerged for diagnosis/evaluation of COPD and its overlap with asthma.

There are remarkable problems in the diagnosis of early interstitial lung diseases with the most important being idiopathic pulmonary fibrosis (IPF), with features of patchy progressive fibrogenesis and generally poor prognosis.
Specific common features in COPD and IPF include their delayed diagnosis, poor response to any therapy, and progressive nature of these diseases.

Research objectives

  • To discover novel, sensitive, and specific combination of non-invasive markers for airway obstructive and parenchymal lung diseases that will have predictive value with respect to disease evaluation, progression, response to treatment, susceptibility to adverse events, and/or to mortality
  • To improve methods for early detection and diagnosis of COPD exacerbations
  • To improve differential diagnostics of COPD and its different clinical phenotypes, such as chronic bronchitis, emphysema and asthma/COPD overlap
  • To better understand the pathogenesis and molecular mechanisms of chronic airway diseases

Ongoing studies and the cohorts

  • Large cohort of asthma, COPD and their overlapping cases that has been followed retrospectively for 6 years and so far prospectively for 4 years; this cohort will be used in the RNA-Seq studies and validation of the proteomic data (cohort from Professor Laitinen).
  • Representative cohorts of heavy smokers followed for 6 years by Jan 2012, collected with Dr Toljamo. Sputum and plasma samples are being used in the validation of the proteomic data.
  • Additional 2 cohorts will include young smokers and non-smokers, and subjects with COPD exacerbations, ongoing in Rovaniemi.
  • Lung tissue samples (paraffin blocks, fresh, RNA later) from various lung diseases (normal lung, healthy smokers, COPD, alpa-1-antitrypsin deficiency lung, IPF) that are of research interest have been systematically collected from 2003.
  • Several national and international collaborations are undergoing in order to test various potential markers of early lung injury based on proteomics and/or hypotheses of lung damage in these specific diseases (pathogenetic mechanisms related to innate immunity, mucus production, fibrogenesis and recent proteomic findings obtained from sputum and lung tissue specimens in our laboratory).

Members of the group
Ville Pulkkinen, PhD, Adjunct Professor, Principal Investigator, University of Helsinki and Helsinki University Central Hospital, Pulmonary Division
Witold Mazur, MD, PhD, Adjunct Professor, Co-leader, Specialist in Pulmonary Medicine and Allergology, Helsinki University Central Hospital and University of Helsinki, Pulmonary Division

PhD student
Jing Gao, MD, University of Helsinki, Young cigarette smokers and asthma/COPD overlap

Laboratory staff:
Tiina Marjomaa, study nurse, University of Helsinki and Helsinki University Central Hospital
Tinja Kanerva, study technician, University of Helsinki

Collaboration
National

  • Tarja Laitinen, Chief and Professor of Pulmonary Medicine, Department of Pulmonary Medicine, Turku University Hospital and University of Turku
  • Tuula Toljamo, MD PhD, Chief Lung Physician, Lapland Central Hospital, Rovaniemi
  • Steffen Ohlmeier, Adj prof, Proteomics Core Facility, Biocenter Oulu, Department of Biochemistry, University of Oulu, Finland; http://www.biochem.oulu.fi/proteomics/
  • Pentti Nieminen, Adj prof, Chief Statistician, University of Oulu, Faculty of Medicine
  • Mikko Rönty, MD PhD, Helsinki University Central Hospital, Department of Pathology
  • Marjukka Myllärniemi, Adjunct Professor, Academy research fellow, Department of Medicine, Pulmonary division, University of Helsinki and Helsinki University Central Hospital
  • Harri Alenius, Research Professor, Finnish Institute of Occupational Health, Helsinki
  • Juha Kere, Professor, Research Programs Unit, Program for Molecular Neurology, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland

International

  • Irfan Rahman, PhD, Associate Professor, University of Rochester, NY, USA
  • Colin Bingle, PhD, University of Sheffield, UK
  • Nobuhisa Ishikawa, MD, PhD, Associate professor, University of Hirosima, Japan
  • Hiroshi Iwamoto, MD PhD, Associate professor, University of Hirosima, Japan
  • Hideo Kobayashi, MD, PhD, National Defense Medical College, Tokorozawa, Japan

Research funding
Major funding for these studies has been granted from Tekes SHOK IMO grant, EVO Funding of HUS, and Research Funds of the University of Helsinki.

Key international peer-reviewed publications (2010 - September 2013)

  • Iwamoto H, Gao J, Koskela J, Kinnula V, Kobayashi H, Laitinen T, Mazur W. Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap. Eur Respir J. 2013 Jun 21.
  • Acevedo N, Sääf A, Söderhäll C, Melen E, Mandelin J, Orsmark-Pietras C, Ezer S, Karisola P, Boije af Gennäs G, Yli-Kauhaluoma J, Alenius H, von Mutius E, Doekes G, Braun-Fahrländer C, Riedler J, van Hage M, Scheyenius A, Pershagen G, Kere J, Pulkkinen V. Interaction of retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma. Plos One, 2013;8(4):e60111.
  • Orsmark-Pietras C, James A, Konradsen J, Nordlund B, Söderhäll C, Pulkkinen V, Pedroletti C, Daham K, Kupczyk M, Dahlén B, Kere J, Dahlén SE, Hedlin G, Melén E. Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics. Eur Respir J. 2013;42:65-78.
  • Pulkkinen V, Säfholm J, Manson M, Adner M, Dahlén SE. The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea. Am J Physiol - Lung Cell Mol Physiol. 2012;303:L956-L966.
  • Ohlmeier S, Mazur W, Linja-Aho A, Louhelainen N, Rönty M, Toljamo T, Bergmann U, Kinnula VL. Sputum proteomics identifies elevated PIGR levels in smokers and mild-to-moderate COPD. J Proteome Res. 2012;11:599-608.
  • Pulkkinen V, Salmenkivi K, Kinnula V, Sutinen E, Halme M, Hodgson U, Lehto J, Jääskeläinen A, Piiparinen H, Kere J, Lautenschlager I, Lappalainen M, Myllärniemi M. A novel screening method detects herpesviral DNA in the idiopathic pulmonary fibrosis lung. Ann Med. 2012;44:178-86.
  • Mazur W, Toljamo T, Ohlmeier S, Vuopala K, Nieminen P, Kobayashi H, Kinnula VL. Elevation of surfactant protein A in plasma and sputum in current cigarette smokers. Eur Respir J. 2011;38:277-284.
  • Pulkkinen V, Bruce S, Rintahaka J, Hodgson U, Laitinen T, Alenius H, Kinnula VL, Myllärniemi M, Matikainen S, Kere J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB J. 2010;24:1167-77.
  • Ishikawa N, Ohlmeier S, Salmenkivi K, , Salmenkivi K, Myllärniemi M, Rahman I, Mazur W, Kinnula VL. Hemoglobin α and β are ubiquitous in the human lung, decline in idiopathic pulmonary fibrosis but not in COPD. Respir Res. 2010;11:123. 2010;11:123.
  • Ohlmeier S, Mazur W, Salmenkivi K, Myllärniemi M, Bergmann U, Kinnula VL. Proteomic studies on receptor for advanced glycation end product variants in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Proteomics Clin Appl. 2010:4:97-105.

Last updated: 2.2.2015