Protean proteases: At the cutting edge of lung diseases

Proteases were traditionally viewed as mere protein-degrading enzymes with a very restricted spectrum of substrates. A major expansion in protease research has uncovered a variety of novel substrates, and it is now evident that proteases are critical pleiotropic actors orchestrating pathophysiological processes. Recent findings evidenced that the net proteolytic activity also relies upon interconnections between different protease and protease inhibitor families in the protease web.In this review, we provide an overview of these novel concepts with a particular focus on pulmonary pathophysiology. We describe the emerging roles of several protease families including cysteine and serine proteases.The complexity of the protease web is exemplified in the light of multidimensional regulation of serine protease activity by matrix metalloproteases through cognate serine protease inhibitor processing. Finally, we will highlight how deregulated protease activity during pulmonary pathogenesis may be exploited for diagnosis/prognosis purposes, and utilised as a therapeutic tool using nanotechnologies.Considering proteases as part of an integrative biology perspective may pave the way for the development of new therapeutic targets to treat pulmonary diseases related to intrinsic protease deregulation

Comparative proteome analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP) and organ donors

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What to expect from the ERS International Congress 2023

For the second consecutive year, the European Respiratory Society (ERS) International Congress will be held in a hybrid format, in Milan, Italy and online, from 9 September to 13 September 2023. This year, the Congress will return to a 5-day programme covering the latest advances in science and clinical practice across the full range of respiratory topics. Thousands of researchers and health professionals will have the opportunity to share their knowledge and work at the world's largest respiratory meeting. In this article, we provide a glimpse of the ERS Congress 2023 including a summary of the Early Career Member (ECM) session, an overview of the Networking EXcellence Training (NEXT) programme, and the “top picks” from the programme selected by the members of the International Congress Programme Committee (ICPC). The full programme is available at: https://www.ersnet.org/congress-and-events/congress/programme/

Mutant KRAS promotes malignant pleural effusion formation

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition

Inhibitoren des Ubiquitin-Proteasom Systems als potentielle Therapeutika bei kardiovaskulären Erkrankungen

The therapeutic potential of proteasome inhibitors as cytostatic drugs was early realized. However, it is the cytotoxic potential of proteasome inhibitors that has long hampered their therapeutic application as nontoxic remedies. Here, we provide evidence that proteasome inhibitors are potential remedies for the therapy of various cardiovascular diseases. While local and pronounced inhibition of the proteasome with high doses of proteasome inhibitors have anti-proliferative, anti-inflammatory and pro-apoptotic effects on vascular smooth muscle cells and suppress development of restenosis in rat carotid arteries, nontoxic and partial inhibition of the proteasome with low inhibitor doses induces a variety of beneficial effects in several different cardiovascular cell types: • reduced expression of collagen isoforms and matrixmetalloproteinases in cardiac fibroblasts, which is associated with suppression of cardiac fibrosis in spontaneous hypertensive rats; • suppressed hypertrophic growth of cardiomyocytes; • enhanced expression of eNOS versus downregulation of ET-1 in endothelial cells leading to improved endothelial function of rat aortic rings; • induction of a conserved stress response with upregulation of hsp70 and several anti-oxidative enzymes in cardiomyocytes and endothelial cells which is associated with protection from thermal and oxidative stress. Our data confirm the concept that proteasome inhibitors are able to act as poisons which induce cell death but also as remedies which modulate cellular function and protect from cell death. To reconcile these divergent effects of proteasome inhibitors we would like to extend the old observation of Paracelsus that “the right dose differentiates a poison and a remedy”, and postulate that for proteasome inhibitors the right dose and cell type differentiate a poison and a remedy: For a given cell type, the degree of proteasome inhibition determines whether the cell dies or is protected from death. While sustained inhibition of multiple sites strongly restricts overall protein turnover and ultimately results in cell death, partial inhibition of only the chymotrypsin-like site may affect degradation of specific sets of substrates and induces a protective stress response. This hypothesis might provide a conceptual framework to pave the way for the clinical application of proteasome inhibitors in other diseases beyond cancer, and in cardiovascular diseases in particular. However, application of proteasome inhibitors is clearly limited for diseases that require chronic treatment, since there is increasing evidence that long-term proteasome impairment may contribute to neurodegenerative disease, cardiac and aortic dysfunction, and aging. For this reason, short-term and/or local treatment with proteasome inhibitors may represent a more feasible approach. In particular, treatment of ischemia- reperfusion injuries and restenosis offer promising clinical applications, as proteasome inhibitors combine acute and local anti-proliferative and anti- inflammatory actions with beneficial systemic effects on endothelial function.Das therapeutische Potential von Proteasominhibitoren als Zytostatika wurde bereits früh erkannt, und verhinderte lange den Einsatz von Proteasominhibitoren als nicht-toxische „Heilmittel“. Die hier dargestellten Daten belegen durch eine Reihe von proof of concept Experimenten, dass Inhibitoren des Proteasoms neue und viel versprechende „Heilmittel“ für die Therapie unterschiedlicher kardiovaskulärer Erkrankungen darstellen. Während die ausgeprägte Hemmung des Proteasoms durch hoch-dosierte Protesominhibitoren deutlich anti-proliferative, anti-inflammatorische und pro-apoptotische Effekte auf glatte Muskelzellen zeigt, die zu einer verminderten Restenose- Ausbildung in Rattenkarotiden beitragen, vermittelt die nicht-toxische und partielle Hemmung des Proteasoms durch niedrig-dosierte Proteasominhibitoren eine Reihe benefizieller Effekte in unterschiedlichen kardiovakulären Zelltypen: • Die reduzierte Expression mehrerer Kollagen Isoformen und Matrixmetalloproteinasen in kardialen Fibroblasten ist assoziiert mit einem deutlich verminderten Grad der kardialen Fibrose in spontan hypertensiven Ratten; • das hypertrophe Wachstum von Kardiomyozyten wird supprimiert; • eine erhöhte Expression von eNOS zusammen mit einer verminderten Expression von ET-1 in Endothelzellen korreliert mit einer verbesserten Endothelfunktion in Rattenaortenringen; • das Auslösen einer konservierten Stress-Antwort mit Hochregulation von hsp70 und der konzertierten Induktion mehrerer anti- oxidativer Enzyme schützt sowohl Endothelzellen wie auch Kardiomyozyten vor thermalen und oxidativem Stress. Unsere Daten sind somit in vollem Einvernehmen mit dem Konzept, dass Proteasominhibitoren als „Gift“ – also als zytotoxische Substanzen - oder „Heilmittel“, welche unterschiedlichste zelluläre Funktionen benefiziell beeinflussen, wirken können. Um diese offensichtlich divergenten zellulären Effekte von Proteasominhibitoren in Einklang zu bringen, lässt sich die Beobachtung von Paracelsus (1493 - 1541) „Alle Dinge sind Gift und nichts ohn Gift, allein die Dosis macht, dass ein Ding kein Gift ist!“ erweitern als nicht nur Dosis- sondern auch Zelltyp- abhängige Wirkung von Proteasominhibitoren: Für einen definierten Zelltyp bestimmt der Grad der Proteasomenhemmung, ob die Zelle stirbt oder vor dem drohenden Zelltod geschützt wird. So führt die gleichzeitige und effektive Hemmung mehrere katalytischer Aktivitäten des Proteasoms zu einem massiv verminderten Proteinumsatz in der Zelle, der - weil nicht mehr kompensierbar - in Apoptose mündet. Demgegenüber könnte eine nur partielle Hemmung der katalytischen Zentren möglicherweise gezielt den Abbau spezifischer Substratgruppen beeinflussen und eine protektive Stress-Antwort auslösen. Diese Hypothese kann als konzeptueller Rahmen für die therapeutische Anwendung von Proteasominhibitoren jenseits der Tumortherapie und insbesondere bei kardiovaskulären Erkrankungen dienen. Der therapeutische Einsatz von Proteasominhibitoren ist dabei jedoch eingeschränkt bei der Behandlung chronischer Erkrankungen. So gibt es eine Reihe von Befunden, die zeigen, dass eine lang anhaltende Einschränkung der proteasomalen Aktivität zur Entwicklung neurodegenerativer und kardiovaskulärer Erkrankungen sowie zu Alterungsprozessen beiträgt. Aus diesem Grund erscheint besonders die kurzzeitige und/oder lokale Anwendung von Proteasominhibitoren Erfolg versprechend, insbesondere die Behandlung von Ischämie/Reperfusionschäden und Restenose. Hier wirken Proteasominhibitoren nicht nur lokal anti-proliferativ und anti-inflammatorisch, sondern auch protektiv und verbessern die endotheliale Funktion im systemischen Kontext

How and to What Extent Immunological Responses to SARS-CoV-2 Shape Pulmonary Function in COVID-19 Patients

International audienceCOVID-19 is a disease caused by a new coronavirus SARS-CoV-2, primarily impacting the respiratory system. COVID-19 can result in mild illness or serious disease leading to critical illness and requires admission to ICU due to respiratory failure. There is intense discussion around potential factors predisposing to and protecting from COVID-19. The immune response and the abnormal respiratory function with a focus on respiratory function testing in COVID-19 patients will be at the center of this Perspective article of the Frontiers in Physiology Series on "The Tribute of Physiology for the Understanding of COVID-19 Disease." We will discuss current advances and provide future directions and present also our perspective in this field

Protein quality control in lung disease: it's all about cloud networking.

Protein quality control involves the comprehensive management of protein function in the cell and is called “proteostasis” [1]. It ranges from translation and chaperone-assisted three-dimensional folding, interaction with protein partners, signal-induced post-translational modifications to disposal by the proteasome or autophagy pathways. Dysfunctional protein quality control is emerging as a key pathogenic mechanism for chronic lung diseases. Two major hereditary conformational disorders of the lung, cystic fibrosis and α1-antitrypsin (α1-AT) deficiency, and some familial forms of idiopathic pulmonary fibrosis (IPF) are caused by the expression of mutant and misfolded proteins that disrupt protein homeostasis and drive the onset of pulmonary diseases [2, 3]. Disturbed proteostasis also causes sporadic respiratory diseases [1, 4]. Cigarette smoke-induced protein misfolding, aberrant proteasomal protein degradation and induction of autophagy have been observed in chronic obstructive pulmonary disease (COPD) patients and smoke-exposed mice [4, 5]. Dysregulation of autophagy and endoplasmic reticulum (ER) stress have also been implicated in cystic fibrosis, pulmonary arterial hypertension, IPF and other lung diseases [6, 7]. Impairment of protein quality control pathways exacerbates the detrimental effects of environmentally induced protein damage in lung pathogenesis [1]. The European Respiratory Society (ERS) research seminar Protein Quality Control in Lung Disease, held on March 1–2, 2014, at Lake Starnberg in Germany, brought together international experts to develop a comprehensive view of protein quality control in general and in the lung in particular. Understanding the complex interplay of protein misfolding, ER homeostasis and protein degradation as interrelated components of adaptive proteostasis will identify novel therapeutic targets for treatment of pulmonary diseases, as outlined here.</p

The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease

Proteasomes comprise a family of proteasomal complexes essential for maintaining protein homeostasis. Accordingly, proteasomes represent promising therapeutic targets in multiple human diseases. Several proteasome inhibitors are approved for treating hematological cancers. However, their side effects impede their efficacy and broader therapeutic applications. Therefore, understanding the biology of the different proteasome complexes present in the cell is crucial for developing tailor-made inhibitors against specific proteasome complexes. Here, we will discuss the structure, biology, and function of the alternative Proteasome Activator 200 (PA200), also known as PSME4, and summarize the current evidence for its dysregulation in different human diseases. We hereby aim to stimulate research on this enigmatic proteasome regulator that has the potential to serve as a therapeutic target in cancer