53 research outputs found
How and to What Extent Immunological Responses to SARS-CoV-2 Shape Pulmonary Function in COVID-19 Patients
COVID-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 âThe Tribute of Physiology for the Understanding of COVID-19 Disease.â We will discuss current advances and provide future directions and present also our perspective in this field
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
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 âtop picksâ 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 kardiovaskulÀren 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: âą reduced expression of collagen isoforms
and matrixmetalloproteinases in cardiac fibroblasts, which is associated with
suppression of cardiac fibrosis in spontaneous hypertensive rats; âą suppressed
hypertrophic growth of cardiomyocytes; âą enhanced expression of eNOS versus
downregulation of ET-1 in endothelial cells leading to improved endothelial
function of rat aortic rings; âą 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 âthe right dose differentiates a poison and a
remedyâ, 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 frĂŒh erkannt, und verhinderte lange den Einsatz von
Proteasominhibitoren als nicht-toxische âHeilmittelâ. Die hier dargestellten
Daten belegen durch eine Reihe von proof of concept Experimenten, dass
Inhibitoren des Proteasoms neue und viel versprechende âHeilmittelâ fĂŒr die
Therapie unterschiedlicher kardiovaskulÀrer Erkrankungen darstellen. WÀhrend
die ausgeprÀgte 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 kardiovakulÀren
Zelltypen: âą 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; âą das hypertrophe Wachstum von Kardiomyozyten wird supprimiert; âą 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 schĂŒtzt sowohl Endothelzellen wie auch Kardiomyozyten vor
thermalen und oxidativem Stress. Unsere Daten sind somit in vollem
Einvernehmen mit dem Konzept, dass Proteasominhibitoren als âGiftâ â also als
zytotoxische Substanzen - oder âHeilmittelâ, welche unterschiedlichste
zellulÀre Funktionen benefiziell beeinflussen, wirken können. Um diese
offensichtlich divergenten zellulÀren Effekte von Proteasominhibitoren in
Einklang zu bringen, lÀsst sich die Beobachtung von Paracelsus (1493 - 1541)
âAlle Dinge sind Gift und nichts ohn Gift, allein die Dosis macht, dass ein
Ding kein Gift ist!â erweitern als nicht nur Dosis- sondern auch Zelltyp-
abhĂ€ngige Wirkung von Proteasominhibitoren: FĂŒr einen definierten Zelltyp
bestimmt der Grad der Proteasomenhemmung, ob die Zelle stirbt oder vor dem
drohenden Zelltod geschĂŒtzt wird. So fĂŒhrt die gleichzeitige und effektive
Hemmung mehrere katalytischer AktivitÀten des Proteasoms zu einem massiv
verminderten Proteinumsatz in der Zelle, der - weil nicht mehr kompensierbar -
in Apoptose mĂŒndet. DemgegenĂŒber 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 fĂŒr die therapeutische Anwendung
von Proteasominhibitoren jenseits der Tumortherapie und insbesondere bei
kardiovaskulÀren Erkrankungen dienen. Der therapeutische Einsatz von
Proteasominhibitoren ist dabei jedoch eingeschrÀnkt bei der Behandlung
chronischer Erkrankungen. So gibt es eine Reihe von Befunden, die zeigen, dass
eine lang anhaltende EinschrÀnkung der proteasomalen AktivitÀt zur Entwicklung
neurodegenerativer und kardiovaskulÀrer Erkrankungen sowie zu
Alterungsprozessen beitrÀgt. Aus diesem Grund erscheint besonders die
kurzzeitige und/oder lokale Anwendung von Proteasominhibitoren Erfolg
versprechend, insbesondere die Behandlung von IschÀmie/ReperfusionschÀden 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 âproteostasisâ [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 1â2, 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
- âŠ