TY - BOOK AB - Respiratory diseases are a major concern in public health, impacting a large population worldwide. Despite the availability of therapies that alleviate symptoms, selectively addressing the critical points of pathopathways remains a major challenge. Innovative formulations designed for reaching these targets within the airways, enhanced selectivity, and prolonged therapeutic effects offer promising solutions. To provide insights into the specific medical requirements of chronic respiratory diseases, the initial focus of this chapter is directed on lung physiology, emphasizing the significance of lung barriers. Current treatments involving small molecules and the potential of gene therapy are also discussed. Additionally, we will explore targeting approaches, with a particular emphasis on nanoparticles, comparing targeted and non-targeted formulations for pulmonary administration. Finally, the potential of inhaled sphingolipids in the context of respiratory diseases is briefly discussed, highlighting their promising prospects in the field. AU - Carneiro, S.* AU - Müller, J.T.* AU - Merkel, O.M. C1 - 68997 C2 - 55167 CY - Gewerbestrasse 11, Cham, Ch-6330, Switzerland SP - 313-328 TI - Targeted molecular therapeutics for pulmonary diseases: Addressing the need for precise drug delivery. JO - Handb. Exp. Pharmacol. VL - 284 PB - Springer International Publishing Ag PY - 2024 SN - 0171-2004 ER - TY - BOOK AB - Since allergic diseases are of great public health relevance, effective primary prevention strategies are urgently needed. This chapter gives an overview of existing primary prevention programs on environmental exposures and dietary strategies based on epidemiological studies which have defined risk- and protective factors for the development of allergic diseases.The allergy protective effect mediated by growing up on a traditional farm environment is well studied. But the exact underlying mechanisms have still not been fully clarified and have not yet led to concrete prevention strategies. The beneficial effect of avoiding cigarette smoke exposure, indoor moisture and molds in pregnancy and childhood on the development of asthma is well documented. Whereas the avoidance of house dust mite exposure is not recommended to prevent eczema or allergy. Dietary supplementation with vitamins, pre- and probiotics in pregnant woman and their offspring is not harmful but evidence for the prevention of allergic diseases is still lacking. Fish oil consumption was shown to be asthma protective. The early introduction of peanuts and egg protein to prevent peanut and egg allergy in children with atopic dermatitis is promising. Further studies are needed to increase the overall evidence in allergy prevention. Most studies lack methodological standards such as randomization and blinding. More evidence is in demand on the potential beneficial impact of multifaceted interventional studies. The future of allergy prevention strategies might be based on individual risk assessment. Therefore, research in the immunological and molecular basis of allergic diseases needs to be promoted. AU - Landgraf-Rauf, K.* AU - von Mutius, E. C1 - 62442 C2 - 50873 SP - 437-448 TI - Effective ways to prevent allergic diseases: Where do we stand? JO - Handb. Exp. Pharmacol. VL - 268 PY - 2022 SN - 0171-2004 ER - TY - BOOK AB - Atopic eczema (AE) is a chronic inflammatory disease hallmarked by intense pruritus and eczematous lesions. It depicts one of the most common skin diseases affecting a major part of children and several percentages of adults.Both pathogenesis and pathophysiology are based on complex orchestrated interactions of skin barrier defects, immunological changes, the environment, and an abundance of other contributing factors. Frequently, AE displays the starting point for other allergic diseases such as allergic asthma and rhinoconjunctivitis. Additionally, the risk of developing food allergy is increased. Furthermore, the disease is accompanied by a susceptibility to bacterial, fungal, and viral infections. The development of new therapies received great impetus by an ample research of the pathophysiological mechanisms, leading to a new era in the treatment of severe atopic eczema due to targeted treatments, e.g. the IL-4R alpha specific monoclonal antibody dupilumab.This article provides an overview of the causative and pathophysiological characteristics, the clinical and diagnostic aspects as well as current and future therapeutical possibilities focusing allergic aspects contributing to the course of the disease. AU - Traidl, S.* AU - Werfel, T.* AU - Traidl-Hoffmann, C. C1 - 62525 C2 - 50907 SP - 101–115 TI - Atopic eczema: Pathophysiological findings as the Beginning of a new era of therapeutic options. JO - Handb. Exp. Pharmacol. VL - 268 PY - 2022 SN - 0171-2004 ER - TY - BOOK AB - The prevalences of allergic diseases, asthma, atopic dermatitis, allergic rhinitis and lately food allergy have been increasing over the last decades. It has been suggested that the prevalence of allergic diseases has reached a plateau in high income countries, while it is still on the rise in low and middle income countries. Generally, allergic diseases more often set on in childhood than in adulthood and affected children contribute more to the rise in allergic disease prevalence than affected adults. Epidemiological evidence suggests that not all atopic dermatitis and asthma cases are attributable to atopic sensitization. Indeed, mainly genetic association studies have prompted the unravelling of barrier dysfunction as a mainstay in the patho-mechanisms leading to atopic dermatitis and to asthma with atopic sensitization secondary to this dysfunction. Epidemiological research on risk and protective factors for allergic disease, acting against the background of genetic susceptibility, has produced an enormous body of evidence. Prominent observations are the 'sibling effect' and the 'farm effect' which gave rise to the 'hygiene hypothesis' and later the 'biodiversity hypothesis'. Future epidemiological research is required to evaluate and refine these hypotheses in light of the paradigm shift from atopic sensitization to barrier dysfunction with ever increasing options for environmental characterization, currently, e.g., 'omics'-techniques in microbiology and metabolism, and with ever increasing options for phenotyping of allergic techniques, including, e.g., high-resolution time series of symptoms using, e.g., sensing technologies. AU - Genuneit, J.* AU - Standl, M. C1 - 62465 C2 - 50888 SP - 21-27 TI - Epidemiology of allergy: Natural course and risk factors of allergic diseases. JO - Handb. Exp. Pharmacol. VL - 268 PY - 2021 SN - 0171-2004 ER - TY - BOOK AB - The main physiological function of the lung is gas exchange, mediated at the interface between the alveoli and the pulmonary microcapillary network and facilitated by conducting airway structures that regulate the transport of these gases from and to the alveoli. Exposure to microbial and environmental factors such as allergens, viruses, air pollution, and smoke contributes to the development of chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. Respiratory diseases as a cluster are the commonest cause of chronic disease and of hospitalization in children and are among the three most common causes of morbidity and mortality in the adult population worldwide. Many of these chronic respiratory diseases are associated with inflammation and structural remodelling of the airways and/or alveolar tissues. They can often only be treated symptomatically with no disease-modifying therapies that normalize the pathological tissue destruction driven by inflammation and remodelling. In search for novel therapeutic strategies for these diseases, several lines of evidence revealed the WNT pathway as an emerging target for regenerative strategies in the lung. WNT proteins, their receptors, and signalling effectors have central regulatory roles under (patho)physiological conditions underpinning lung function and (chronic) lung diseases and we summarize these roles and discuss how pharmacological targeting of the WNT pathway may be utilized for the treatment of chronic lung diseases. AU - Hu, Y.* AU - Ciminieri, C.* AU - Hu, Q. AU - Lehmann, M. AU - Königshoff, M. AU - Gosens, R.* C1 - 62858 C2 - 51113 SP - 305-336 TI - WNT signalling in lung physiology and pathology. JO - Handb. Exp. Pharmacol. VL - 269 PY - 2021 SN - 0171-2004 ER - TY - BOOK AB - The skin barrier provides us with several lines of protection from outside hazards. Its most outward layers, the stratum corneum and the epidermis seal our body with an acidic, dry, and rather cool surface, hostile to microbes. Yet, there are also fine-tuned interactions between the mostly commensal microbiota on top of the skin surface, with underlying epidermal cells as well as the immune system, to preserve a healthy steady state and to initiate repair processes when necessary. We take a concise look at the recent insights on the inner workings of this complex barrier. AU - Köberle, M.* AU - Amar, Y.* AU - Hölge, I.M.* AU - Kaesler, S.* AU - Biedermann, T. C1 - 62349 C2 - 50800 SP - 43-52 TI - Cutaneous barriers and skin immunity. JO - Handb. Exp. Pharmacol. VL - 268 PY - 2021 SN - 0171-2004 ER - TY - BOOK AB - T helper (Th) and regulatory T (Treg) cells represent important effectors of adaptive immunity. They mediate communication between the immune system and tissue sites and thereby coordinate effective defense against environmental threats or maintain tolerance, respectively. Since the discovery of two prototypic T helper cells, Th1 and Th2, additional phenotypic and functional distinct subsets have been described ranging from Th17, Th22, Th9, and T follicular helper cells. The same holds true for regulatory T cells that represent a family with functionally distinct subsets characterized by co-expression of the transcription factors T-bet, Gata3, or RORγt. Here, we summarize the current knowledge on differentiation and function of T helper and regulatory T cell subsets and discuss their lineage stability versus plasticity towards other subsets. In addition, we highlight the direct and indirect contribution of each subset to the pathology of allergies and indicate novel therapies for specific targeting the effector functions of T helper and regulatory T cells. AU - Ohnmacht, C. AU - Eyerich, S. C1 - 62510 C2 - 50896 SP - 265-296 TI - Diversity of T helper and regulatory T cells and their contribution to the pathogenesis of allergic diseases. JO - Handb. Exp. Pharmacol. VL - 268 PY - 2021 SN - 0171-2004 ER - TY - BOOK AB - Over the last few decades, allergic diseases have been steadily increasing worldwide, a phenomenon that is not yet completely understood. Recent evidence, however, suggests that alterations in the microbiome may be a contributing factor. The microbiome refers to all microorganisms in a habitat including bacteria, fungi, and viruses. Using modern sequencing technologies, we are now capable of detecting and analyzing the human microbiome in more detail than ever before. Epidemiological and experimental studies have indicated that a complex intestinal microbiome supports the development of the immune system during childhood, thus providing protection from allergic diseases, including food allergy. The microbiome becomes an important part of human physiology and forms dynamic relationships with our various barrier systems. For example, bacterial dysbiosis is a hallmark of atopic eczema and correlates with disease progression. Similarly, the lung and nasopharyngeal microbiome is altered in patients with asthma and allergic rhinitis. While these results are interesting, the underlying mechanisms are still unclear and need to be investigated with functional studies. This review gives a short overview of the terminology and methods used in microbiome research before highlighting results concerning the lung, skin, and intestinal microbiome in allergic diseases. AU - Schwierzeck, V.* AU - Hülpüsch, C. AU - Reiger, M. C1 - 62409 C2 - 50847 TI - Microbiome of barrier organs in allergy: Who runs the world? Germs! JO - Handb. Exp. Pharmacol. PY - 2021 SN - 0171-2004 ER - TY - JOUR AB - Brown adipose tissue (BAT), the specialized heat-producing organ found in many placental mammals including humans, may be accessible for clinical drug intervention to help combat metabolic diseases. Understanding the biology of BAT and its thermogenic uncoupling protein 1 (UCP1) will benefit from an assessment of its evolution, answering where UCP1 originated and how it has been modified and integrated into cellular energy metabolism. Here, we review topical insights regarding the molecular evolution of UCP1-also reconstructing the proximate and ultimate factors selecting for brown fat thermogenesis in placental mammals. This new thinking on "old" events will assist our understanding of how thermogenic mitochondrial uncoupling was integrated into the physiology of the brown adipocyte. Recent comparative studies examining the occurrence of UCP1 in vertebrates not only identified the ancient (pre-mammal) rise of UCP1 but also its repeated downfall during mammalian evolution as evidenced by multiple independent gene loss and/or inactivation events. Together with the comparative physiology of various species, we may be able to find conditions that favor UCP1 thermogenesis and, learning from these insights, identify molecular networks that will be useful to pharmacologically stimulate the tissue. AU - Gaudry, M.J.* AU - Campbell, K.L.* AU - Jastroch, M. C1 - 55886 C2 - 46635 SP - 127-141 TI - Evolution of UCP1. JO - Handb. Exp. Pharmacol. VL - 251 PY - 2019 SN - 0171-2004 ER - TY - BOOK AB - Using standardized guidelines in preclinical research has received increased interest in light of recent concerns about transparency in data reporting and apparent variation in data quality, as evidenced by irreproducibility of results. Although the costs associated with supporting quality through a quality management system are often obvious line items in laboratory budgets, the treatment of the costs associated with quality failure is often overlooked and difficult to quantify. Thus, general estimations of quality costs can be misleading and inaccurate, effectively undervaluing costs recovered by reducing quality defects. Here, we provide examples of quality costs in preclinical research and describe how we have addressed misconceptions of quality management implementation as only marginally beneficial and/or unduly burdensome. We provide two examples of implementing a quality management system (QMS) in preclinical experimental (animal) research environments – one in Europe, the German Mouse Clinic, having established ISO 9001 and the other in the United States, the University of Kentucky (UK), having established Good Laboratory Practice-compliant infrastructure. We present a summary of benefits to having an effective QMS, as may be useful in guiding discussions with funders or administrators to promote interest and investment in a QMS, which ultimately supports shared, mutually beneficial outcomes. AU - Littrell, O.M.* AU - Stoeger, C. AU - Maier, H. AU - Fuchs, H. AU - Cassis, L.A.* AU - Gerhardt, G.A.* AU - Grondin, R.* AU - Gailus-Durner, V. C1 - 56951 C2 - 47343 SP - 399-423 TI - Costs of implementing quality in research practice. JO - Handb. Exp. Pharmacol. VL - 257 PY - 2019 SN - 0171-2004 ER - TY - BOOK AU - Pfeifer, A.* AU - Klingenspor, M.* AU - Herzig, S. C1 - 55955 C2 - 46677 TI - Preface. JO - Handb. Exp. Pharmacol. VL - 251 PY - 2019 SN - 0171-2004 ER - TY - JOUR AB - Brite/brown adipose tissue (BAT) is a thermogenic tissue able to dissipate energy via non-shivering thermogenesis. It is naturally activated by cold and has been demonstrated to increase thermogenic capacity, elevate energy expenditure, and to ultimately contribute to fat mass reduction. Thus, it emerges as novel therapeutic concept for pharmacological intervention in obesity and other metabolic disorders. Therefore, the comprehensive understanding of the regulatory network in thermogenic adipocytes is in demand.The surprising findings that (1) all human protein-coding genes make up not more than 2% of our genome, (2) organismal complexity goes well along with the percentage of nonprotein-coding sequences, and that (3) three quarters of our genome are pervasively transcribed, provide evidence that noncoding RNAs (ncRNAs) are not junk, but a significant and even predominant part of our transcriptome representing a treasure chest worth retrieving regulatory determinants in biological processes and diseases.In this chapter, the impact of regulatory small and long ncRNAs (lncRNAs) in particular microRNAs and lncRNAs on BAT formation and metabolic function and their involvement in physiological and pathological conditions has been reviewed. AU - Scheideler, M. C1 - 55888 C2 - 46634 SP - 215-237 TI - Regulatory small and long noncoding RNAs in brite/brown adipose tissue. JO - Handb. Exp. Pharmacol. VL - 251 PY - 2019 SN - 0171-2004 ER - TY - JOUR AB - MSOT has revolutionized biomedical imaging because it allows anatomical, functional, and molecular imaging of deep tissues in vivo in an entirely noninvasive, label-free, and real-time manner. This imaging modality works by pulsing light onto tissue, triggering the production of acoustic waves, which can be collected and reconstructed to provide high-resolution images of features as deep as several centimeters below the body surface. Advances in hardware and software continue to bring MSOT closer to clinical translation. Most recently, a clinical handheld MSOT system has been used to image brown fat tissue (BAT) and its metabolic activity by directly resolving the spectral signatures of hemoglobin and lipids. This opens up new possibilities for studying BAT physiology and its role in metabolic disease without the need to inject animals or humans with contrast agents. In this chapter, we overview how MSOT works and how it has been implemented in preclinical and clinical contexts. We focus on our recent work using MSOT to image BAT in resting and activated states both in mice and humans. AU - Karlas, A. AU - Reber, J. AU - Liapis, E. AU - Paul-Yuan, K. AU - Ntziachristos, V. C1 - 53738 C2 - 44967 TI - Multispectral optoacoustic tomography of brown adipose tissue. JO - Handb. Exp. Pharmacol. PY - 2018 SN - 0171-2004 ER - TY - JOUR AB - Diabetes constitutes an increasing threat to human health, particularly in newly industrialized and densely populated countries. Type 1 and type 2 diabetes arise from different etiologies but lead to similar metabolic derangements constituted by an absolute or relative lack of insulin that results in elevated plasma glucose. In the last three decades, a set of new medicines built upon a deeper understanding of physiology and diabetic pathology have emerged to enhance the clinical management of the disease and related disorders. Recent insights into insulin-dependent and insulin-independent molecular events have accelerated the generation of a series of novel medicinal agents, which hold the promise for further advances in the management of diabetes. In this chapter, we provide a historical context for what has been accomplished to provide perspective for future research and novel emerging treatment options. AU - Clemmensen, C. AU - Müller, T.D. AU - Finan, B. AU - Tschöp, M.H. AU - DiMarchi, R.* C1 - 44479 C2 - 36948 SP - 437-459 TI - Current and emerging treatment options in diabetes care. JO - Handb. Exp. Pharmacol. VL - 233 PY - 2016 SN - 0171-2004 ER - TY - BOOK AB - Ghrelin is the only potent orexigenic peptide in circulation. It stimulates food intake and leads to positive energy balance, adipogenesis, and body weight gain. However, the physiological significance of ghrelin in the regulation of energy homeostasis is controversial, since loss of ghrelin function in rodents does not necessarily lead to anorexia and weight loss. In this chapter, we discuss the metabolic function of ghrelin and are highlighting recent findings including the discovery and function of ghrelin-acylating enzyme ghrelin O-acyltransferase (GOAT). Based on available published data, we conclude that ghrelin is a principally important endogenous regulator of energy balance, which however may affect both food intake and systemic metabolism via independent mechanisms. Importantly, ghrelin, when acylated by GOAT, might represent a key molecular link between the sensing of consumed calories and the neuroendocrine control of energy homeostasis. Thus, agents antagonizing the action of ghrelin may have therapeutic potential in the therapy of obesity. AU - Kirchner, H.* AU - Heppner, K.M.* AU - Tschöp, M.H. A2 - Joost, H.-G.* C1 - 11135 C2 - 30513 CY - Berlin SP - 161-184 TI - The role of ghrelin in the control of energy balance. JO - Handb. Exp. Pharmacol. VL - 209 PB - Springer PY - 2012 SN - 0171-2004 ER - TY - BOOK AB - This chapter describes the major gene therapeutic approaches for viral infections. The vast majority of published approaches target severe chronic viral infections such as hepatitis B or C and HIV infection. Two basic gene therapy strategies are introduced here. The first involves the expression of a protein or an RNA that inhibits viral replication by targeting crucial steps of the viral life cycle or by interfering with a cellular factor required for virus replication. The major limitation of this approach is that primary levels of gene modification have generally not been sufficient to reduce the availability of target cells permissive for virus replication to a level that significantly decreases overall viral load. Thus, investigators have banked on the expectation that gene-protected cells have a sufficient selective advantage to accumulate and gain prevalence over time, a prediction that so far could not be confirmed in clinical trials. In vivo levels of gene modification can be improved, however, by introducing an additional selectable marker. In addition, a secreted antiviral gene product that exerts a bystander effect could significantly reduce overall virus replication despite relatively low levels of gene modification. In addition to these direct antiviral approaches, several strategies have been developed that employ or aim to enhance host immune responses. The innate immune response has been enhanced, for example, by the in vivo expression of interferons. Alternatively, T cells can be grafted with recombinant receptors to boost adaptive virus-specific immunity. These approaches are especially promising for chronic virus infection, where natural immune responses are evidently not sufficient to effectively control virus replication. AU - von Laer, D.* AU - Baum, C.* AU - Protzer, U. A2 - Kräusslich, H.G.* ; Bartenschlager, R.* C1 - 1840 C2 - 26833 CY - Berlin SP - 265-297 TI - Antiviral gene therapy. JO - Handb. Exp. Pharmacol. VL - 189 PB - Springer PY - 2009 SN - 0171-2004 ER - TY - BOOK AB - Optical imaging techniques offer simplistic while highly sensitive modalities for molecular imaging research. In this chapter, the major instrumental necessities for microscopic and whole-animal imaging techniques are introduced. Subsequently, the resulting imaging modalities using visible or near-infrared light are presented and discussed. The aim is to show the current capabilities and application fields of optics. AU - Schulz, R.B. AU - Semmler, W.* A2 - Semmler, W.* ; Schwaiger, M.* C1 - 9096 C2 - 26013 CY - Berlin; Heidelberg SP - 3-22 TI - Fundamentals of Optical Imaging. JO - Handb. Exp. Pharmacol. VL - 185 IS - 1 PB - Springer PY - 2008 SN - 0171-2004 ER - TY - BOOK AU - Wegener, E. AU - Krappmann, D. A2 - Klussmann, E.* ; Scott, J.* C1 - 9125 C2 - 25385 CY - Berlin SP - 237-259 TI - Dynamic protein complexes regulate NF-kB signaling. JO - Handb. Exp. Pharmacol. VL - 186 PB - Springer PY - 2008 SN - 0171-2004 ER - TY - BOOK AU - Kühn, R. AU - Streif, S. AU - Wurst, W. A2 - Heffter, A.* ; Heubner, W.* ; Schüller, J.* C1 - 3403 C2 - 24139 CY - Berlin [u.a.] SP - 147-174 TI - RNA interference in mice. JO - Handb. Exp. Pharmacol. VL - 178 PB - Springer PY - 2007 SN - 0171-2004 ER - TY - BOOK AB - In contrast to the haematopoietic system in which each cell type is subject to constant turnover, thus endowing this system with the permanent ability to reconstitute itself, the nervous system has long been known as an organ devoid of spontaneous cellular reconstitution. Yet the discovery that certain regions of the mammalian central nervous system do sustain neurogenesis throughout life, together with the fact that cells can be isolated from the adult brain that generate neurons in vitro, has led to the idea that the nervous tissue harbours neural stem cells. The term “neural stem cell” has now become associated with enormous expectations for curing diseases of the nervous system. Yet many of the biological fundamentals of neural stem cells need to be revealed before these expectations can be properly judged or even fulfilled. This begins with the question of whether the neural stem cell corresponds to a real entity or rather represents an in vitro dedifferentiation phenomenon. In this chapterwe attempt to give an overviewof our current knowledge of the biology of the presumable adult neural stem cell. This is followed by a comparative assessment of the possibilities of using adult neural stemcells and embryonic stem cells for therapeutic approaches in the context of neurodegenerative diseases. Finally, we will look at the “evil side” of stemness by discussing the evidence that brain cancersmay originate from cells with stem cell-like properties. AU - Berninger, B. AU - Hack, M.A. AU - Götz, M. C1 - 4758 C2 - 28372 CY - Berlin SP - 319-360 TI - Neural stem cells: On where they hide, in which disguise, and how we may lure them out. JO - Handb. Exp. Pharmacol. VL - 174 PB - Springer PY - 2006 SN - 0171-2004 ER -