Asthma and chronic obstructive pulmonary disease (COPD) are major inflammatory lung diseases.
René Lutter, PhD
The outstanding issues in relation to treatment, prognosis and cure of asthma and COPD are:
- no adequate treatment of acute worsening of symptoms (exacerbation),
- unresponsiveness to mainstay of treatment, i.e. corticosteroids, and
- tissue remodelling as a consequence of chronic, severe inflammation.
Our basic research efforts are aimed at understanding the molecular mechanisms in inflammation that underlie the exaggerated inflammatory response during an exacerbation, unresponsiveness to corticosteroids and the chronicity of inflammation.
Sarcoidosis is a relatively rare granulomatous disease that in about 25% of diagnoses develops into a chronic or progressive disease. It is unclear which molecular mechanisms determine resolution or perseverance of granulomas. In that context we are addressing the involvement of the immuno-regulatory enzyme indoleamine 2,3-dioxygenase.
Details on these basic research lines are provided below (click on Controlling Inflammation). There are opportunities within our basic research projects for university students (Medical Biology, Medicine) and HLO students (lab technicians) to perform an internship (click on Internships). Our research efforts constitute an integral part of the main research interests of the Department of Respiratory Medicine and thus there is a close collaboration with clinicians and the lung function lab. For these studies we are continuously seeking volunteers (healthy or with mild to moderate asthma) to participate in these studies (if you are interested, please click on Inflammation during an exacerbation). In addition to the basic research we guide and facilitate the laboratory part of clinical studies and we contribute to the diagnosis of interstitial lung diseases and severe asthma. These activities are performed within our CCKL-accredited lab LONI.
The inflammatory process is critical for eradicating endogenous and exogenous challenges and thus for maintaining health. When, however, the extent of inflammation is not in balance with the challenge, inflammation can turn into a potential threat. Too much inflammation can cause tissue destruction whereas too little inflammation may lead to the persistence of the inflammatory stimulus. In either case, this may lead to more inflammation. To balance the inflammatory process, every aspect of inflammation is tightly regulated. This starts at the level of the production of inflammatory mediators that drive inflammation, till the resolution of inflammation by down-regulating inflammatory cell numbers.
Cells within the lungs such as epithelial cells and fibroblasts are key players in producing inflammatory mediators. The expression of inflammatory mediators is tailored to ensure an adequate but limited inflammatory response, causing as little collateral tissue damage as possible. To that end, expression of inflammatory mediators is controlled transcriptionally as well as post-transcriptionally, which involves mRNA degradation and translational control. Our previous studies have indicated that post-transcriptional control (particularly mRNA degradation) of inflammatory mediator expression by lung structural cells is easily disturbed. In fact, interleukin(IL)-17, which has been implicated in chronic and severe inflammation in several inflammatory diseases among which asthma, directly attenuates degradation of mRNAs that encode for inflammatory mediators. This leads to hyperresponsive inflammatory mediator production and under certain conditions even to unresponsiveness to corticosteroids. Dr. Saheli Chowdhury's studies have revealed that mRNA decay of a number of key inflammatory mediators depends on two pathways, the ARE-mediated mRNA decay pathway and that directed by microRNAs. IL-17 attenuates both mRNA decay pathways by reducing the contribution of the microRNA pathway and changing the relative contribution of various proteins (AUBp) that bind to the AU-rich (AUUUA) elements, preventing its degradation (Figure 1).
More recent studies have revealed that there may be a defect in these regulatory pathways in bronchial epithelial cells from patients with asthma. Current studies are aimed at delineating this defect and at unravelling the molecular machinery involved in these pathways.
Inflammation during an exacerbation
Respiratory viral infections are a major cause of acute worsening (exacerbation) of asthma and COPD symptoms. In addition, inflammatory responses tend to be corticosteroid unresponsive during an exacerbation. The underlying mechanisms are still unclear although we assume that there is a relation with the defect observed in bronchial epithelial cells from patients with asthma, described above. We exploit a human challenge model in which human volunteers are exposed to a common cold virus (Rhinovirus 16) to induce a mild cold in healthy individuals and a mild exacerbation in patients with asthma. In combination with relevant experimental animal and in vitro studies we aim to delineate the cause for these excerbations and focus on the role of eosinophilic granulocytes and the underlying process that leads to corticosteroid unresponsiveness. These studies are performed by Dr. Suzanne Bal and Dr. Lara Ravanetti, part of which involves an intervention with anti-IL-5. Patients with mild to moderate asthma and healthy controls who are interested to participate in these highly relevant clinical studies can find more information here:
Resolution of inflammation
Foreign (non-self) material that the immune system fails to eradicate, typically will be walled off in well-organized inflammatory tissue structures called granulomas. These granulomas protect the host by containing the enclosed antigen and limiting inflammation.
Granulomas are manifest in various infectious and non-infectious diseases, like tuberculosis, leprosy, sarcoidosis, chronic granulomatous disease (CGD) and Crohn’s disease. The mechanisms that control resolution, persistence and progression of granulomas are still largely unknown.
The inducible enzyme indoleamine 2,3-dioxygenase (IDO) depletes tryptophan and produces kynurenine. The depletion of tryptophan and the generation of kynurenine and related metabolites have been implicated in dampening T cell responses by promoting apoptosis or preventing activation of T cells. We and others have found that IDO activity also dampens responses by neutrophils and macrophages. Since tryptophan is also an essential amino acid for most micro-organisms, IDO-mediated depletion of tryptophan can also affect microbial metabolism and even kill microbes. This led us to propose that granulomatous IDO may limit local inflammation and may prevent bacterial growth/dissemination.
Based upon studies in murine tuberculosis and analyses of clinical specimens from patients with CGD, sarcoidosis or tuberculosis, we conclude that IDO activity determines whether granuloma resolve, are stable or become progressive. High granulomatous IDO activity induces moderate to severe apoptosis of immune and inflammatory cells that may prevent the clearance of the micro-organisms/antigen and leading to persistent and progressive granuloma. Low IDO activity leads to resolution of the granulomas. If, however, these granulomas enclose live pathogens this also causes dissemination of pathogens and aggravate inflammation. Our current studies are aimed at exploring this concept (Figure 2) further.
Kuijpers T, Lutter R. Inflammation and repeated infections in CGD: two sides of a coin. Cell Mol Life Sci. 2012 Jan;69(1):7-15.
Wösten-van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, van Goor H, Kamilic J, Florquin S, Bos AP. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011 Dec;225(4):618-27.
Fan XY, van den Berg A, Snoek M, van der Flier LG, Smids B, Jansen HM, Liu RY, Lutter R. Arginine deficiency augments inflammatory mediator production by airway epithelial cells in vitro. Respir Res. 2009 Jul 3;10:62
van der Sluijs KF, Nijhuis M, Levels JH, Florquin S, Mellor AL, Jansen HM, van der Poll T, Lutter R. Influenza-induced expression of indoleamine 2,3-dioxygenase enhances interleukin-10 production and bacterial outgrowth during secondary pneumococcal pneumonia. J Infect Dis. 2006;193(2):214-22.
van den Berg A, Freitas J, Keles F, Snoek M, van Marle J, Jansen HM, Lutter R. Cytoskeletal architecture differentially controls post-transcriptional processing of IL-6 and IL-8 mRNA in airway epithelial-like cells. Exp Cell Res. 2006;312(9):1496-506.
van den Berg A, Snoek M, Jansen HM, Lutter R. E1A expression dysregulates IL-8 production and suppresses IL-6 production by lung epithelial cells. Respir Res. 2005;6:111.
van den Berg A, Kuiper M, Snoek M, Timens W, Postma DS, Jansen HM, Lutter R. IL-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells. Am J Respir Cell Mol Biol. 2005;33(1):97-104.
Roger T, Bresser P, Snoek M, Van Der Sluijs K, Van Den Berg A, Nijhuis M, Jansen HM, Lutter R. Exaggerated IL-8 and IL-6 responses to TNF-a by parainfluenza virus type 4-infected NCI-H292 cells. Am J Physiol Lung Cell Mol Physiol. 2004;287(5):L1048-55.
van der Sluijs KF, van Elden LJ, Nijhuis M, Schuurman R, Pater JM, Florquin S, Goldman M, Jansen HM, Lutter R, van der Poll T. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol. 2004;172(12):7603-9.
van Wissen M, Snoek M, Smids B, Jansen HM, Lutter R. IFN-gamma amplifies IL-6 and IL-8 responses by airway epithelial-like cells via indoleamine 2,3-dioxygenase. J Immunol. 2002;169(12):7039-44.
Some older key papers:
Bresser P, van Alphen L, Lutter R. New strains of bacteria and exacerbations of COPD. N Engl J Med. 2002;347(25):2077-9;
Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria. Abrahams JP, Leslie AG, Lutter R, Walker JE. Nature. 1994;370(6491):621-8
Crystallization of F1-ATPase from bovine heart mitochondria. Lutter R, Abrahams JP, van Raaij MJ, Todd RJ, Lundqvist T, Buchanan SK, Leslie AG, Walker JE. J Mol Biol. 1993;229(3):787-90
A new method for detecting endocytosed proteins. EMBO J. 1988;7(13):4087-92. Bretscher MS, Lutter R.
For a full list with publication click here.
Our group has a long track record of supervising national and international (Socrates, Erasmus) students with their research projects. We have excellent lab facilities, a broad experience with cell and molecular biology approaches (see references), and pay attention to interpreting and presenting data and setting up experiments. Besides work discussions and a journal club discussing recent articles, there are a number of meetings each week giving you the opportunity to meet more leading, national and international scientists. If you are interested in our topics and would like to do a research project, please contact Dr. René Lutter (E-mail: firstname.lastname@example.org ; Phone: +31-20-5668753) for further information. We have also developed a broad expertise on the analyses of material from clinical studies (bronchoalveolar lavage fluid, sputum (spontaneous and induced), breath condensate and of blood) using ELISA's, multiplex assays and other immunological assays (Elispot), enzymatic assays, quantitative mRNA assays and the detection of cell surface and intracellular markers (FACS, intracellular detection).
Rene Lutter: email@example.com
or telephone +31-20-5668753