[Show abstract][Hide abstract] ABSTRACT: We report the case of a young female lung transplant recipient with difficult-to-treat cytomegalovirus (CMV) disease. While treatment with intravenous (IV) ganciclovir failed due to antiviral drug resistance, a trial with foscarnet resulted in severe side effects. In addition, the patient received IV CMV-specific immune globulins as adjunctive therapy and leflunomide as experimental therapy. In this context, CMV-specific immune monitoring was performed and was successfully implemented in management decisions. The patient was screened for acquisition of an adaptive immune response, and antiviral prophylaxis and therapy was tailored according to results. This report highlights the impact of CMV-specific immune monitoring on individualized therapy for appropriate prophylaxis and management of CMV infection and diseases.
International Journal of Infectious Diseases. 09/2014;
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung diseases (ILD) are often associated with pulmonary hypertension (PH). This study aimed to evaluate the therapeutic benefit of phosphodiesterase-5 (PDE-5) inhibitors in pulmonary hypertension secondary to ILD.
Patients with ILD and PH were treated with sildenafil or tadalafil. Right heart catheterization was performed before and after a minimum of 3-month treatment. In addition, lung function, 6-min walk distance (6MWD) and plasma brain natriuretic peptide (BNP) concentration were assessed.
Ten ILD patients (three female, mean age 64.4 ± 9.0 years, six with idiopathic pulmonary fibrosis (IPF), four with hypersensitivity pneumonitis, (HP)) with significant precapillary PH (mean pulmonary artery pressure (PAPm) ≥ 25 mmHg, pulmonary vascular resistance (PVR) > 280 dyn*s*cm(-5) ; pulmonary artery wedge pressure (PAWPm) ≤ 15 mmHg) were treated with either sildenafil (n = 5) or tadalafil (n = 5). Pulmonary haemodynamics were severely impaired at baseline (PAPm 42.9 ± 5.4 mmHg; cardiac index (CI) 2.7 ± 0.6 L/min/m(2) ; PVR 519 ± 131 dyn × sec × cm(-5) ). After mean follow-up of 6.9 ± 5.8 months an increase in CI (2.9 ± 0.7 L/min/m(2) , P = 0.04) and a decrease in PVR (403 ± 190 dyn × sec × cm(-5) , P = 0.03) were observed. 6MWD and BNP did not change significantly.
Our data suggest that treatment with PDE-5 inhibitors improves pulmonary haemodynamic patients with PH secondary to ILD.
[Show abstract][Hide abstract] ABSTRACT: As one of the most common infectious diseases pneumonia is associated with a high morbidity and mortality. A rapid and rational diagnostic work-up is crucial to improve patient prognosis and outcome. The diagnosis of pneumonia requires the detection of pulmonary infiltrates; therefore, radiological methods are a key part of the diagnostic algorithm to demonstrate the presence of infiltrates and to confirm the diagnosis. The accepted standard method is chest X-ray at two levels, posteroanterior (PA) and lateral radiographs. Computed tomography is mainly used for immunocompromised patients, patients with pre-existing structural lung disease, therapy refractory pneumonia and in the differential diagnosis of suspected underlying diseases, such as pulmonary embolism or malignancy. Increasing evidence suggests that lung ultrasound is a promising, precise technology which is readily available and with no irradiation of patient.
[Show abstract][Hide abstract] ABSTRACT: The TLR7 agonist imiquimod has been used successfully as adjuvant for skin treatment of virus-associated warts and basal cell carcinoma. The effects of skin TLR7 triggering on respiratory leukocyte populations are unknown. In a placebo-controlled experimental animal study we have used multicolour flow cytometry to systematically analyze the modulation of respiratory leukocyte subsets after skin administration of imiquimod. Compared to placebo, skin administration of imiquimod significantly increased respiratory dendritic cells (DC) and natural killer cells, whereas total respiratory leukocyte, alveolar macrophages, classical CD4+ T helper and CD8+ T killer cell numbers were not or only moderately affected. DC subpopulation analyses revealed that elevation of respiratory DC was caused by an increase of respiratory monocytic DC and CD11b(hi) DC subsets. Lymphocyte subpopulation analyses indicated a marked elevation of respiratory natural killer cells and a significant reduction of B lymphocytes. Analysis of cytokine responses of respiratory leukocytes after stimulation with Klebsiella pneumonia indicated reduced IFN-γ and TNF-α expression and increased IL-10 and IL-12p70 production after 7 day low dose skin TLR7 triggering. Additionally, respiratory NK cytotoxic activity was increased after 7d skin TLR7 triggering. In contrast, lung histology and bronchoalveolar cell counts were not affected suggesting that skin TLR7 stimulation modulated respiratory leukocyte composition without inducing overt pulmonary inflammation. These data suggest the possibility to modulate respiratory leukocyte composition and respiratory cytokine responses against pathogens like Klebsiella pneumonia through skin administration of a clinically approved TLR7 ligand. Skin administration of synthetic TLR7 ligands may represent a novel, noninvasive means to modulate respiratory immunity.
PLoS ONE 01/2012; 7(8):e43320. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to create a prognostic score calculated one yr after LTX based on post-transplant factors inclusive of donor and recipient characteristics that could be used to predict long-term survival in patients after lung transplantation (LTX).
Uni- and multivariate analysis in 206 consecutive LTX patients identified independent risk factors for post-transplant mortality and onset of bronchiolitis obliterans syndrome. Munich-LTX-Score is devised by summing up each identified risk factor.
Multivariate analyses revealed acute rejection, lymphocytic bronchiolitis, donor age ≥ 55 yr, and HLA-A ≥ 2-/DR ≥ 2 mismatch and single LTX to be independent negative predictors for long-term survival (p < 0.05). Munich-LTX-Score identified three discrete groups: low-, moderate-, and high risk. The actuarial five-yr survival after score calculation one yr after LTX of the entire cohort was 58%, compared with 91% in low-, 54% in moderate-, and 0% in the high-risk group (p < 0.001).
Within our cohort of patients calculation of the Munich-LTX-Score, consisting of donor-, recipient-, and post-transplant characteristics, one yr after LTX allowed to predict long-term survival of lung transplant recipients. After prospective validation, this score could identify patients who may benefit from intensified surveillance after LTX.
[Show abstract][Hide abstract] ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus in progressive LAM.
Sirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 ± 11.9 years) with documented progression. Serial pulmonary function tests and six-minute-walk-distance (6-MWD) assessments were performed.
The mean loss of FEV1 was -2.30 ± 0.52 ml/day before therapy and a significant mean gain of FEV1 of 1.19 ± 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV1 and FVC at baseline were 1.12 ± 0.15 l (36.1 ± 4.5%pred.) and 2.47 ± 0.25 l (69.2 ± 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV1 and FVC was demonstrated (3 months ΔFEV1: 220 ± 82 ml, p = 0.024; 6 months ΔFEV1: 345 ± 58 ml, p = 0.001); (3 months ΔFVC: 360 ± 141 ml, p = 0.031; 6 months ΔFVC: 488 ± 138 ml, p = 0.006). Sirolimus was discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy.
Our data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimus administration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation of sirolimus is mandatory prior to lung transplantation.
Respiratory research 01/2011; 12:66. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow-up of 3 months: (1) stable non-BOS, (2) unstable non-BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non-BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non-BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.
American Journal of Transplantation 11/2010; 11(1):129-37. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a frequent indication for lung transplantation (LTX) with pulmonary hypertension (PH) negatively affecting outcome. The optimal procedure type remains a debated topic. The aim of this study was to evaluate the impact of pretransplant PH in IPF patients. Single LTX (SLTX, n = 46) was the standard procedure type. Double LTX (DLTX, n = 30) was only performed in cases of relevant PH or additional suppurative lung disease. There was no significant difference for pretransplant clinical parameters. Preoperative mean pulmonary arterial pressure was significantly higher in DLTX recipients (22.7 +/- 0.8 mmHg vs. 35.9 +/- 1.8 mmHg, P < 0.001). After transplantation, 6-min-walk distance and BEST-FEV(1) were significantly higher for DLTX patients (6-MWD: 410 +/- 25 m vs. 498 +/- 23 m, P = 0.02; BEST-FEV(1): 71.2 +/- 3.0 (% pred) vs. 86.2 +/- 4.2 (% pred), P = 0.004). Double LTX recipients demonstrated a significantly better 1-year-, overall- and Bronchiolitis obliterans Syndrome (BOS)-free survival (P < 0.05). Cox regression analysis confirmed SLTX to be a significant predictor for death and BOS. Single LTX offers acceptable survival rates for IPF patients. Double LTX provides a significant benefit in selected recipients. Our data warrant further trials of SLTX versus DLTX stratifying for potential confounders including PH.
Transplant International 03/2010; 23(9):887-96. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral blood monocytes (PBMo) originate from the bone marrow, circulate in the blood and emigrate into various organs where they differentiate into tissue resident cellular phenotypes of the mononuclear phagocyte system, including macrophages (Mphi) and dendritic cells (DC). Like in other organs, this emigration and differentiation process is essential to replenish the mononuclear phagocyte pool in the lung under both inflammatory and non-inflammatory steady-state conditions. While many studies have addressed inflammation-driven monocyte trafficking to the lung, the emigration and pulmonary differentiation of PBMo under non-inflammatory conditions is much less understood.
In order to assess the transcriptional profile of circulating and lung resident mononuclear phagocyte phenotypes, PBMo, lung Mphi and lung DC from naïve mice were flow-sorted to high purity, and their gene expression was compared by DNA microarrays on a genome-wide scale. Differential regulation of selected genes was validated by quantitative PCR and on protein level by flow cytometry.
Differentially-expressed genes related to cell traffic were selected and grouped into the clusters (i) matrix metallopeptidases, (ii) chemokines/chemokine receptors, and (iii) integrins. Expression profiles of clustered genes were further assessed at the mRNA and protein levels in subsets of circulating PBMo (GR1- vs GR1+) and lung resident macrophages (alveolar vs interstitial Mphi). Our data identify differentially activated genetic programs in circulating monocytes and their lung descendents. Lung DC activate an extremely diverse set of gene families but largely preserve a mobile cell profile with high expression levels of integrin and chemokine/chemokine receptors. In contrast, interstitial and even more pronounced alveolar Mphi, stepwise downregulate gene expression of these traffic relevant communication molecules, but strongly upregulate a distinct set of matrix metallopetidases potentially involved in tissue invasion and remodeling.
Our data provide new insight in the changes of the genetic profiles of PBMo and their lung descendents, namely DC and Mphi under non-inflammatory, steady-state conditions. These findings will help to better understand the complex relations within the mononuclear phagocyte pool of the lung.
Respiratory research 02/2009; 10:2. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine involved in acute lung injury and other processes such as wound repair and tumor growth. MIF exerts pro-proliferative effects on a variety of cell types including monocytes/macrophages, B cells, and gastric epithelial cell lines through binding to the major histocompatibility complex type II-associated invariant chain, CD74. In acute lung injury, inflammatory damage of the alveolar epithelium leads to loss of type I alveolar epithelial cells (AEC-I), which are replaced by proliferation and differentiation of type II alveolar epithelial cells (AEC-II). In this study we have investigated the potential of MIF to contribute to alveolar repair by stimulating alveolar epithelial cell proliferation. We show that murine AEC-II, but not AEC-I, express high surface levels of CD74 in vivo. Culture of AEC-II in vitro resulted in decreased mRNA levels for CD74 and loss of surface CD74 expression, which correlated with a transition of AEC-II to an AEC-I-like phenotype. MIF stimulation of AEC-II induced rapid and prolonged phosphorylation of ERK1/2 and Akt, increased expression of cyclins D1 and E, as well as AEC-II proliferation. Corresponding MIF signaling and enhanced thymidine incorporation was observed after MIF stimulation of MLE-12 cells transfected to overexpress CD74. In contrast, MIF did not induce MAPK activation, gene transcription, or increased proliferation in differentiated AEC-I-like cells that lack CD74. These data suggest a previously unidentified role of MIF-CD74 interaction by inducing proliferation of AEC-II, which may contribute to alveolar repair.
[Show abstract][Hide abstract] ABSTRACT: Mononuclear phagocytes have been attributed a crucial role in the host defense toward influenza virus (IV), but their contribution to influenza-induced lung failure is incompletely understood. We demonstrate for the first time that lung-recruited "exudate" macrophages significantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced pneumonia. Using CC-chemokine receptor 2-deficient (CCR2(-/-)) mice characterized by defective inflammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of influenza-infected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL messenger RNA was found to be markedly up-regulated in alveolar exudate macrophages as compared with peripheral blood monocytes. Moreover, among the different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate macrophages resulted in significantly reduced AEC apoptosis, attenuated lung leakage, and increased survival upon IV infection. Collectively, these findings demonstrate a key role for exudate macrophages in the induction of alveolar leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by TRAIL-expressing macrophages is identified as a major underlying mechanism.
Journal of Experimental Medicine 01/2009; 205(13):3065-77. · 13.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interferon-alpha (IFN-alpha) has a critical role in antiviral immunity and plasmacytoid dendritic cells (pDCs) have been demonstrated as the principal IFN-alpha source after Toll-like receptor (TLR) 7 and 9 stimulation. Little is known about the contribution of pDC-independent IFN-alpha sources to total IFN-alpha production capacity of human peripheral blood. Using an array of pathogen associated molecular patterns (PAMPs), Poly(I:C)/Dotap represented the second strongest IFN-alpha stimulus in total PBMC. Poly(I:C)/Dotap induced three times more IFN-alpha, when compared to TLR7-stimulation (R848) and four times less, when compared to TLR9-stimulation. Dotap (mediator of cellular uptake) dramatically increased Poly(I:C)-induced IFN-alpha production. Sorting experiments and ELISpot assays revealed that monocytes and not myeloid DCs are the main IFN-alpha source after Poly(I:C)/Dotap stimulation. ELISpot analyses demonstrated the highest IFN-alpha spot numbers after Poly(I:C)/Dotap stimulation. Although pDCs produced highest IFN-alpha levels per cell, monocytes represent a competing IFN-alpha source in total PBMC due to their high frequency.
[Show abstract][Hide abstract] ABSTRACT: The presentation of self antigens by dendritic cells (DC) plays an important role in the initiation and maintenance of autoimmunity. In a model of experimental autoimmune orchitis (EAO), we have previously characterized dominant testicular autoantigens and shown an increase in DC numbers during the course of disease. In this study, we have developed a protocol for the isolation of a highly pure population of DC ( approximately 97%) from the testis of EAO and control rats to analyse the expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules (CD80, CD86), chemokine receptors (CCR2, CCR7) and cytokines (IL-10, IL-12p70, TNF-alpha). By flow cytometry, we observed similar percentage and intensity levels of MHC class II, CD80 and CD86 expression in testicular DC in all groups. Moreover, by real-time RT-PCR we have detected significantly higher CCR7 mRNA level in isolated testicular DC from rats with EAO compared to controls, whereas the expression of CCR2 was decreased in orchitis. Transcripts of IL-12p40 were observed in DC from all groups, whereas the expression of IL-10 and the rate limiting IL-12 subunit p35 were detectable exclusively in testicular DC from the inflamed testes. In co-culture experiments, testicular DC isolated from EAO animals significantly enhanced naïve T-cell proliferation compared with control DC. Taken together these results suggest that testicular DC in control testis is not mature and functionally tolerogenic, whereas in EAO testis, IL-12 expression and stimulation of T-cell proliferation points to a mature immunogenic state prior imminent migration to the lymph nodes to amplify immune responses against testicular antigens.
Molecular Human Reproduction 01/2008; 13(12):853-61. · 4.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Strategically located beneath the alveolar epithelial barrier, dendritic cells (DCs) of the lung are centrally involved in the sampling and processing of inhaled antigens. However, the contribution of DCs to acute lung inflammation induced by inhaled bacterial toxins is largely unknown.
To determine the effect of increased lung DC numbers elicited by Fms-like tyrosine kinase-3 ligand (Flt3L) on the acute lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) and Klebsiella pneumoniae infection.
Mice were pretreated with Flt3L either in the absence or presence of anti-CD11a antibodies to block the Flt3L-elicited lung DC accumulation or were made transiently neutropenic and then challenged with E. coli LPS or K. pneumoniae.
Flt3L-pretreated mice challenged with LPS responded with drastically increased numbers of both lung parenchymal and alveolar DCs together with an aggravated neutrophilic alveolitis, elevated tumor necrosis factor-alpha and IL-12 levels, and a strongly increased lung permeability compared with LPS- or Flt3L-only-treated mice. Anti-CD11a-mediated blockade of lung DC accumulation significantly attenuated the lung permeability developing in response to LPS, whereas transient neutropenia did not affect lung permeability changes. Finally, Flt3L-pretreated mice responded with increased lung permeability and decreased survival upon infection with K. pneumoniae.
Lung DCs actively participate in the early inflammatory response to both inhaled bacterial toxins and live bacteria and play a yet unrecognized role in regulating lung barrier integrity.
American Journal of Respiratory and Critical Care Medicine 12/2007; 176(9):892-901. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte beta(1) and beta(2) integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-alpha-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical beta(1) and beta(2) integrins but also junctional adhesion molecule pathways.
The Journal of Immunology 09/2006; 177(3):1817-24. · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dendritische Zellen (DC) sind wichtige Regulatoren des Immunsystems und sind zentral in die Abwehrfunktion der Lunge integriert. Sie sind in enger Nachbarschaft zu den großen Atemwegen und den Alveolen lokalisiert und phagozytieren und prozessieren kontinuierlich Antigene. Viele Aspekte der DC-Biologie in der Lunge und ihrer Rolle in der adaptiven Immunantwort sind eingehend untersucht worden; ihre Rolle in akuten Entzündungsreaktionen wie der akuten bakteriellen Pneumonie ist hingegen bisher kaum bekannt. DC sind mit einer einzigartigen Vielzahl von Rezeptoren des angeborenen Immunsystems bestückt und sind außerdem in der Lage, innerhalb der ersten Stunden nach Antigenkontakt große Mengen proinflammatorischer und immunregulatorischer Zytokine zu produzieren. Dieses wirft die Frage auf, inwieweit DC an Initiierung und Verlauf der frühen Phase einer bakteriellen Pneumonie beteiligt sind. Nur teilweise bekannt ist ferner der Beitrag verschiedener Adhäsionsmoleküle zur Rekrutierung von DC in die Lunge unter Ruhe- und Entzündungsbedingungen.
Zur Beantwortung dieser Fragen wurden Mäuse systemisch mit Fms-like tyrosine kinase-3-Ligand (Flt3L), dem wichtigsten in vivo-Wachstumsfaktor für die DC-Differenzierung, behandelt. Der Beitrag verschiedener Adhäsionsmoleküle zur DC-Rekrutierung wurde durch Gabe von funktionsblockierenden monoklonalen Antikörpern untersucht. Die Gabe von Flt3L führte zu einer starken Anreicherung von DC in der Lunge; diese Rekrutierung war abhängig von beta2-Integrinen, während die Blockade des beta1-Integrins CD29/CD49d und seines Interaktionspartners VCAM-1 keinen blockierenden Effekt hatte.
Die intratracheale Gabe von Lipopolysaccharid führte in Flt3L-vorbehandelten Mäusen zu einem dramatisch verstärkten Entzündungsphänotyp im Vergleich zu den Kontrollen, ablesbar an einer deutlich höheren Zahl von Leukozyten im Lungengewebe und in der bronchoalveolären Lavage, einem moderaten TNF-alpha- und dramatischen IL-12-Anstieg und einer schweren Schädigung der alveolokapillären Schrankenfunktion. Diese aggravierte Entzündung konnte durch eine Blockade der DC-Anreicherung in der Lunge durch anti-CD11a-Antikörper auf das Niveau der kontroll-behandelten Mäuse reduziert werden, persistierte aber nach einer Depletion der neutrophilen Granulozyten. Dieses zeigt eine neue, bisher unbekannte Bedeutung von DC für die Regulation der Schrankenfunktion in der Lunge. Diese Befunde konnten in einem Infektionsmodell mit Klebsiella pneumoniae bestätigt werden. Auch in diesem Modell zeigte sich eine starke Verstärkung der Entzündungsantwort in Flt3L-vorbehandelten Tieren, zudem wiesen diese Tiere eine deutlich erhöhte Mortalität gegenüber den Kontrolltieren auf.
In der Zusammenschau zeigen die Ergebnisse der vorliegenden Untersuchung eine neue, bisher unbekannte Funktion von DC der Lunge in der Initiierung und der frühen Phase bakterieller Pneumonien. Darüberhinaus erweitern und modifizieren diese hier präsentierten Ergebnisse das bisher bekannte pathophysiologische Bild dieser wichtigen Erkrankung. Dendritic cells (DCs) are important regulators of the immune system and are critically involved in the immunosurveillance of the lung. They reside in close proximity to both the large airways and the alveoli and constantly take up and process antigen. While many aspects of lung DC biology in adaptive immune responses have been addressed, their role in acute bacterial pneumonia is less well understood. Their unique equipment with receptors and effector molecules of the innate immune system, however, and their capacity to produce large amounts of both proinflammatory and immuneregulatory cytokines within the first hours after antigen contact raises the question of the contribution of lung DC to the initiation and course of the early phase of bacterial pneumonia. Another question that has been only partially adressed is the contribution of the different adhesion molecules for DC recruitment to the lung under non-inflammatory and inflammatory conditions.
To address these questions, mice were treated systemically with Fms-like tyrosine kinase-3 ligand (Flt3L), the most important in vivo growth factor for DC proliferation and differentiation. The contribution of adhesion molecules were analyzed by coapplication of function-blocking monoclonal antibodies against various adhesion molecules. Flt3L treatment of mice elicited a strong lung DC accumulation that was mainly dependent on beta2 integrins, blockade of which led to a >80% reduction of DC numbers in lung homogenates. In contrast, blockade of both beta1 integrin CD29/CD49d and VCAM-1 did not affect Flt3L elicited lung DC accumulation.
Intratracheal challenge with lipopolysaccharide resulted in a much more severe inflammatory response in the lung of Fl3L pretreated than of vehicle-treated mice, as demonstrated by increased leukocyte numbers in lung tissue and bronchoalveolar lavage; moderately increased TNF-alpha and dramatically increased IL-12 levels; and, most importantly, a severe aggravation of the lung leakage. This aggravated inflammation could be inhibited by anti-CD11a-mediated inhibition of Flt3L elicited lung DC accumulation, but persisted after depletion of neutrophils, indicating a novel, hitherto unrecognized role of lung DC in the regulation of the lung barrier integrity. Importantly, these findings could be confirmed in Klebsiella pneumoniae infection model, where Flt3L pretreated mice did not only exhibit a severely aggravated inflammation, but also an increased mortality compared to vehicle-treated mice.
Taken together, the results of this study shed a new light on the role of lung DC in the initiation and the early phase of acute bacterial pneumonia, and expand and partially redefine the pathophysiologic concept of acute lung inflammation.
American Journal of Respiratory and Critical Care Medicine, 176, 2007, S. 892-901.