Pulmonary Alveolar Proteinosis and new therapeutic concepts

 

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Abstract

Pulmonary alveolar proteinosis (PAP) is an umbrella term used to refer to a pulmonary syndrome which is characterized by excessive accumulation of surfactant in the lungs of affected individuals. In general, PAP is a rare lung disease affecting children and adults, although its prevalence and incidence is variable among different countries. Even though PAP is a rare disease, it is a prime example on how modern medicine can lead to new therapeutic concepts, changing ways and techniques of (genetic) diagnosis which ultimately led into personalized treatments, all dedicated to improve the function of the impaired lung and thus life expectancy and quality of life in PAP patients. In fact, new technologies, such as new sequencing technologies, gene therapy approaches, new kind and sources of stem cells and completely new insights into the ontogeny of immune cells such as macrophages have increased our understanding in the onset and progression of PAP, which have paved the way for novel therapeutic concepts for PAP and beyond. As of today, classical monocyte-derived macrophages are known as important immune mediator and immune sentinels within the innate immunity. Furthermore, macrophages (known as tissue resident macrophages (TRMs)) can also be found in various tissues, introducing e. g. alveolar macrophages in the broncho-alveolar space as crucial cellular determinants in the onset of PAP and other lung disorders. Given recent insights into the onset of alveolar macrophages and knowledge about factors which impede their function, has led to the development of new therapies, which are applied in the context of PAP, with promising implications also for other diseases in which macrophages play an important role. Thus, we here summarize the latest insights into the various forms of PAP and introduce new pre-clinical work which is currently conducted in the framework of PAP, introducing new therapies for children and adults who still suffer from this severe, potentially life-threatening disease.

Zusammenfassung

Pulmonale Alveolar Proteinose (PAP) ist ein Überbegriff für ein pulmonales Syndrom, das durch die übermäßige Akkumulation von Surfactant in den Lungen von betroffenen Patienten gekennzeichnet ist. PAP ist eine seltene Erkrankung, die sowohl Kinder als auch Erwachsene betrifft und deren Prävalenz und Inzidenz stark zwischen verschiedenen Ländern variiert. Obwohl die PAP eine seltene Erkrankung ist, so ist diese Krankheit ein gutes Beispiel wie Fortschritte in der modernen Medizin zu neuen therapeutischen Ansätzen und veränderten Methoden und Techniken in der genetischen Diagnostik führen, welches schlussendlich die Lungenfunktion der Patienten verbessern und somit eine höhere Lebenserwartung und gesteigerte Lebensqualität der Patienten ermöglichen. Zum besseren Verständnis in der Krankheitsentstehung haben aktuelle Technologien wie neuste Genomsequenzierung, moderne Gentherapieansätze, Möglichkeiten der Stammzellgewinnung sowie neuste Erkenntnisse in der Ontogenese von Immunzellen wie beispielsweise Makrophagen, maßgeblich dazu beigetragen die Lebensqualität von Patienten zu verbessern. Damit wurde der Weg für neue therapeutische Ansätze in der Behandlung von PAP geebnet, aber auch ein großer Beitrag zum allgemeinen wissenschaftlichen Verständnis erbracht. Im Bereich der PAP und als wesentliche Grundlage in der Krankheitsentstehung haben sich klassische, aus Monozyten differenzierte Makrophagen als wichtiger Wächter und Modulator der angeborenen Immunabwehr etabliert. Darüber hinaus sind auch gewebespezifische Makrophagen (tissue resident macrophages, TRM) in nahezu allen Geweben, so auch der Lunge, des menschlichen Körpers zu finden und gewinnen im medizinischen Kontext zunehmend an Bedeutung. So spielen beispielsweise die Alveolar-Makrophagen, die im broncho-alveolären Raum angesiedelt sind, eine tragende Rolle in der Pathophysiologie von PAP sowie weiteren Lungenerkrankungen. Nicht nur in der Behandlung von PAP sind daher die neuen Erkenntnisse über die Funktionsweise und mögliche Funktionseinschränkungen der Alveolar-Makrophagen wegweisend für neue Behandlungskonzepte, sondern bieten auch große Chancen für moderne Therapieansätze in der Behandlung von weiteren Krankheiten in denen Makrophagen relevant zur Krankheitsentstehung beitragen. Aus diesem Grund werden in dieser Übersichtsarbeit die neuesten wissenschaftlichen Erkenntnisse über die verschiedenen Formen von PAP sowie aktuelle präklinische Untersuchungen im Kontext von PAP zusammentragen und die neuen Behandlungsmöglichkeiten vorstellen.

^* Authors contributed equally

Publication History

Received: 02 November 2023
Received: 28 November 2023

Accepted: 15 December 2023

Article published online:
29 January 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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