Lutz Wollin

• PhD
• Researcher at Boehringer Ingelheim

Sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies characterized by progressive muscle weakness and disability. Sarcoglycan deficiency induces instability of the sarcolemma during muscle contraction leading to muscle fiber loss and its replacement by fibro-adipose tissue. Therapies able to reduce the fibro-fatty expansion...

Introduction A larger group of patients with differing clinical interstitial lung diseases (ILD) develop a progressive fibrosing (PF-ILD) phenotype during the course of their disease despite immunosuppressive therapy. The kinase inhibitor nintedanib is approved for the treatment of the most agressive fibrosing ILD, idiopathic pulmonary fibrosis (IP...

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal interstitial lung disease. Actually, no treatment can block or reverse the development of lung fibrosis in patients suffering from IPF. The discovery of new antifibrosing drugs remains thus an area of intensive research. Arsenic trioxide (ATO), a safe and effective pro-oxidant...

The chemokine CXCL13 controls the normal organization of secondary lymphoid tissues and the neogenesis of ectopic lymphoid structures in nonlymphoid organs, particularly the lungs. The progression and severity of idiopathic pulmonary fibrosis (IPF), a fatal and irreversible interstitial lung disease, is predicted by the circulating blood concentrat...

Introduction: In the airways, spleen tyrosine kinase (Syk) promotes inflammation, collagen deposition, smooth muscle cell proliferation and contraction (Tabeling, C. et al. Allergy 2017 Jul;72(7):1061-1072). As yet, the role of Syk in the pulmonary vasculature remains elusive. Here, we studied Syk expression and function in the pulmonary vasculatur...

Poor translation from animal studies to human clinical trials is one of the main hurdles in the development of new drugs. Here, we used precision-cut kidney slices (PCKS) as a translational model to study renal fibrosis and to investigate whether inhibition of tyrosine kinase receptors, with the selective inhibitor nintedanib, can halt fibrosis in...

Objectives: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF) and was demonstrated to slow disease progression in patients with IPF by reducing decline in forced vital capacity by 50%. Recently, nintedanib has been reported to exert anti-fibrotic activity on systemic sclerosis (scleroderma, SSc) skin fibroblasts and t...

A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fib...

The tyrosine kinase inhibitor, Nintedanib (NTD), has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In cell-free systems, NTD was recently shown to inhibit kinase activity of the human recombinant colony-stimulating factor 1 (CSF1) receptor (CSF1R) which mediates major functions of pulmonary macrophages. In the present stud...

Interstitial lung disease is a common manifestation of systemic sclerosis. Systemic sclerosis–associated interstitial lung disease is characterized by progressive pulmonary fibrosis and a reduction in pulmonary function. Effective treatments for systemic sclerosis–associated interstitial lung disease are lacking. In addition to clinical similaritie...

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and...

Einleitung: Die intrazelluläre Nicht-Rezeptor-Tyrosinkinase Syk reguliert in den Atemwegen Inflammation sowie glattmuskuläre Proliferation und Kontraktion (Tabeling, C. et al. Allergy 2017 Jul;72(7):1061 – 1072). Hier analysierten wir die Expression und Funktion von Syk in der pulmonalen Zirkulation und untersuchten eine mögliche Beteiligung von Sy...

Introduction: In the airways, spleen tyrosine kinase (Syk) promotes inflammation, smooth muscle cell proliferation and contraction (Tabeling, C. et al. Allergy 2017 Jul;72(7):1061-1072). However, little is known about the expression and role of Syk in the vascular compartment of the lung. Here, we analyzed Syk expression and function in the pulmona...

Introduction: In the airways, spleen tyrosine kinase (Syk) is a central promoter of inflammation, collagen deposition, smooth muscle cell proliferation and contraction (Tabeling, C. et al. Allergy 2017 Jul;72(7):1061-1072). To date, little is known about the role of Syk in the pulmonary vasculature. In this study, we investigated Syk expression and...

Aims Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors, such as PDGF, FGF and VEGF. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine...

Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process....

Objectives: Pharmacological inhibition of spleen tyrosine kinase (Syk) is generally well tolerated in humans. In the airways, Syk is known to promote inflammation, smooth muscle cell proliferation and contraction. However, its expression and function in the pulmonary vasculature and its possible involvement in the pathogenesis of pulmonary arterial...

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) develops in approximately 20% of patients with RA. SKG mice, which are genetically prone to developing autoimmune arthritis, develop a pulmonary interstitial pneumonia that resembles human cellular and fibrotic non-specific interstitial pneumonia. Nintedanib, a tyrosine kinase inhib...

Background & Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Activated fibroblasts are the key effector cells in fibrosis, producing excessive amounts of collagen and extracellular matrix (ECM) proteins. Whether the extracellular matrix (ECM) conditioned by IPF fibroblasts determines the phenotype o...

Einleitung: Syk ist eine intrazellulare Nicht-Rezeptor-Tyrosinkinase, die jüngst als zentraler Mediator glattmuskulärer Konstriktion identifiziert wurde. Ob Syk eine funktionelle Rolle in der pulmonalen Vasokonstriktion ausübt und sich hieraus mögliche therapeutische Implikationen für die pulmonalarterielle Hypertonie (PAH) ableiten lassen, ist geg...

Aim of the study: The prevention and treatment of chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx) remain unsatisfactory. Growth factors may play an important role in the development of CLAD. This study evaluated the effects of nintedanib, a receptor tyrosine kinase inhibitor, in the treatment of CLAD after experimental L...

Background: Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-re...

Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5 mg/kg). N...

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease. After many drugs failed in clinical trials, improvements in the understanding of the pathogenesis of IPF led to the approval of two drugs that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the sea...

Background and purpose: Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of β2 -adrenergic receptors (β2 -AR) has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of β2 -AR agonism has...

Background: Nintedanib has anti-fibrotic and anti-inflammatory activity and is approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to noninvasively assess the efficacy of nintedanib in a mouse model of partial lung irradiation to prevent radiation-induced lung damage (RILD). Methods: 266 C57BL/6 adult male mice...

Rationale: Spleen tyrosine kinase (Syk) has been implicated as a mediator of smooth muscle cell contraction independent of its immunomodulatory functions. Its role in pulmonary vasoconstriction and pulmonary arterial hypertension (PAH)-associated pulmonary vascular hyperresponsiveness, however, remains unknown. Methods: In human and murine lung tis...

Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between di...

Nintedanib (BIBF 1120) was approved for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014 after it had received a breakthrough designation from the Food and Drug Administration during clinical development. It is one of the two effective treatment modalities currently on the market for patients with IPF. In the same year, nintedanib recei...

Background: Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allerg...

Background: The long-acting β2-agonist (LABA) olodaterol was shown to have anti-fibrotic activity in primary human lung fibroblasts (Herrmann et al, Eur Respir J. 2014;44:Suppl.58) however, its anti-fibrotic in vivo efficacy has not yet been demonstrated. Aim: To test the effect of olodaterol in a mouse model of bleomycin induced lung fibrosis. Met...

RATIONALE: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a progressive and debilitating disease without effective therapies. SKG mice, genetically prone to develop autoimmune arthritis, develop a pulmonary interstitial pneumonia that resembles aspects of human RA-ILD. Nintedanib, a specific tyrosine kinase inhibitor, is appr...

BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment...

BI 1002494 is a novel, potent and selective SYK inhibitor with sustained plasma exposure following oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting FcϵR1-mediated mast cell and basophil degranulation (IC50= 115 nM) compared to B-cell receptor me...

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and is characterized by a poor prognosis, with an estimated 5-year survival of approximately 20%. Progressive and irreversible lung functional impairment leads to chronic respiratory insufficiency with a severely impaired quality of life. In the last 2...

Background: Nintedanib and pirfenidone were recently authorized for the treatment of idiopathic pulmonary fibrosis (IPF) in the US and EU. Nintedanib is a tyrosine kinase inhibitors targeting also PDGFRα/β, FGFR1-3 and VEGFR1-3. In contrast, the molecular target of pirfenidone is currently unknown. Lung fibroblast proliferation is accepted as a fun...

Background: Nintedanib a tyrosine kinase inhibitor for PDGFRα and β, FGFR1-3, VEGFR1-3 and Src-family kinaseshas been shown to slow disease progression in idiopathic pulmonary fibrosis (IPF) and has recently been authorized for the treatment of IPF in the US and EU. Objectives: To analyze the anti-fibrotic activity of nintedanib in models of pulmon...

Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clini...

β2 -agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting β2 -agonist olodaterol to inhibit pulmonary inflammation and to shed light on its ant...

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which th...

Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platele...

The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis (IPF). To explore its mode of action, nintedanib was tested in human lung fibroblasts and mouse models of lung fibrosis. Human lung fibroblasts expressing PDGF-receptor-α and -β were stimulated with PDGF-BB. Receptor ac...

The multidrug resistance protein 4 (Mrp4) is an ATP-binding cassette transporter that is capable of exporting the second messenger cAMP from cells, a process that might regulate cAMP-mediated anti-inflammatory processes. However, using LPS- or cigarette smoke (CS)-inflammation models, we found that neutrophil numbers in the bronchoalveolar lavage f...

The spleen tyrosine kinase (Syk) is a key mediator of immunoreceptor signaling in immune cells. Thus, interfering with the function of Syk by genetic deletion or pharmacological inhibition might influence a variety of allergic and autoimmune processes. Since conventional Syk knockout mice are not viable, studies addressing the effect of Syk deletio...

Tiotropium bromide is a long acting muscarinic antagonist (LAMA), marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD). Besides its proven direct bronchodilatory activity, recent clinical studies demonstrated that tiotropium is able to reduce the exacerbation rate and impact the clinical course of...

Inhibitory effects of roflumilast on responses characteristic of allergic asthma were investigated in a fungal asthma model in BALB/c mice. Mice were sensitized with Aspergillus antigen (Afu) and exposed to Afu or vehicle, and given roflumilast 1 or 5 mg/kg. Early airway response (EAR) and late airway hyperresponsiveness (AHR) to methacholine were...

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with...

This study investigated the effects of roflumilast, a PDE4 inhibitor, on slow-reacting substance of anaphylaxis (SRS-A)-mediated bronchoconstriction and pulmonary leukotriene (LT) release in ovalbumin (OVA)-sensitized and -challenged guinea pigs. Animals were treated with roflumilast orally (0.04, 0.12, 0.4, or 4 mg/kg) or placebo 1 hour before OVA...

Rationale: There is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease. Objectives: This study evaluated the effects of roflumilast, a phospho-diesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice. Methods: Roflumilast wa...

There is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease. This study evaluated the effects of roflumilast, a phosphodiesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice. Roflumilast was given orally either at 1 mg/kg...

RationaleBronchial asthma is characterized by infiltration of immuno-competent cells and release of pro-inflammatory mediators into the airways. These phenomena are seen also in ovalbumin (OVA)-sensitized and OVA-challenged animals. Roflumilast, a novel, potent, selective PDE4 inhibitor has demonstrated anti-inflammatory activity and is in clinical...

Phosphodiesterase (PDE) inhibitors have potential as alternatives or adjuncts to glucocorticoid therapy in asthma. We compared roflumilast (a selective PDE4 inhibitor) with pentoxifylline (a nonselective inhibitor) and dexamethasone in ameliorating the lesions of chronic asthma in a mouse model. BALB/c mice sensitized to ovalbumin were chronically...

Unlabelled: The effects of additional i.v. therapy with a cyclooxygenase-inhibitor Eltenac to a recombinant surfactant protein C (rSP-C) based surfactant were investigated in a rat lung lavage model of acute lung injury. Treatment was done at 60 min after the induction of acute lung injury by lavage. The influence of the different treatments were...

Background Orally available small molecular weight compounds with ability to suppress the proinflammatory mediator Tumour Necrosis Factor alpha (TNF) are of high interest for the treatment of rheumatoid arthritis (RA). Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) is a highly potent and selective inhibit...

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide), a novel, highly potent, and selective phosphodiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast and its N-oxide, the primary metabolite in vivo, with...

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used to ameliorate neutropenia in patients after antineoplastic treatment. It has also been suggested as an adjunct treatment in septic patients; however, the recruitment and priming of leukocytes by GM-CSF bears the hazard of a hyperinflammatory response. In particular, the role of GM-CS...

The lungs are the remote organ most commonly affected in human peritonitis. The major goals of this study were to define the dose- and time-dependent relationship between graded septic peritonitis and systemic and pulmonary inflammatory responses in mice. BALB/c mice were treated with intraperitoneal polymicrobial inoculi and sacrificed at 3, 12, a...

The aim of this study was to relate changes in rat lung functions caused by the endotoxin lipopolysaccharide (LPS) to alterations in structure. The following four experimental groups were used: 1), control in vitro, perfusion for 150 minutes; 2), LPS in vitro, perfusion for 150 minutes and infusion of 5 mg of LPS after 40 minutes; 3), control ex vi...

This study was carried out to further clarify the role of eicosanoids in platelet-activating factor (PAF)-induced pulmonary vasoconstriction, bronchoconstriction, and edema formation in the isolated perfused rat lung. Infusion of PAF into the isolated perfused rat lung caused vasoconstriction [mean effective concn (EC50) = 0.88 nmol], caused bronch...

This article will describe a method for perfusing and ventilating rat lungs which allows assessment of lung mechanics, segmental vascular resistance, gas exchange, and vascular permeability. Isolated perfused rat lungs (IPL) were ventilated by negative pressure ventilation and were perfused at constant pressure with recirculating, albumin-containin...