H παρουσίαση αυτή αποτελεί δημιουργία του ομιλητή Παρακαλείστε να τη χρησιμοποιήσετε μόνο για ενημέρωσή σας

H παρουσίαση αυτή αποτελεί δημιουργία του ομιλητή Παρακαλείστε να τη χρησιμοποιήσετε μόνο για ενημέρωσή σας

ΕΝΟΤΗΤΑ 1: Διαγνωστικά προβλήματα και χειρισμοί

Ορισμός και Παθοφυσιολογία Βρογχικού άσθματος: Η σύγχρονη άποψη Ευφροσύνη Μάναλη Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών

Προβληματισμοί Το βρογχικό άσθμα αποτελεί μία χρόνια διαταραχή των αεραγωγών και συνιστά μείζον κοινωνικό πρόβλημα υγείας σε όλες τις χώρες του κόσμου. Αφορά σε άτομα όλων των ηλικιών, μπορεί να έχει πολύ βαριά κλινική εικόνα και μερικές φορές μπορεί να οδηγήσει στον θάνατο Global Strategy for Asthma Management and Prevention Updated 2012 www.ginasthma.org

Ορισμός του άσθματος Το άσθμα είναι μια χρόνια φλεγμονώδης διαταραχή των αεραγωγών στην οποία παίζουν ρόλο πολλά κύτταρα και παράγοντες κυτταρικής προέλευσης Η χρόνια φλεγμονή προκαλεί αύξηση της βρογχικής υπεραντιδραστικότητας, που οδηγεί σε υποτροπιάζοντα επεισόδια συριγμού, δύσπνοιας, σφιξίματος στο στήθος και βήχα, ιδιαίτερα τη νύχτα ή νωρίς το πρωί Αυτά τα επεισόδια σχετίζονται συνήθως με εκτενή, αλλά ποικίλλουσα απόφραξη της ροής του αέρα που είναι συχνά αναστρέψιμη

An estimated 300 million people worldwide suffer from asthma, with 250,000 annual deaths attributed to the disease. Approximately 250,000 people die prematurely each year from asthma. Almost all of these deaths are avoidable.

Παγκόσμια Διακύμανση στον Επιπολασμό Συμπτωμάτων Άσθματος International Study of Asthma and Allergies in Children (ISAAC) Lancet 1998;351:1225 The prevalence of asthma in different countries varies widely, but the disparity is narrowing due to rising prevalence in low and middle income countries and plateauing in high income countries

Ομάδα άσθματος Ελληνικής Πνευμονολογικής Εταιρείας: 2632 άτομα 8.6% του γενικού πληθυσμού πάσχουν από άσθμα www.myasthma.gr

Bronchial asthma Bronchial asthma is a disorder of the conducting airways that contract too easily or too much to cause variable airflow obstruction with symptoms of wheeze, cough, chest tightness and shortness of breath Holgate ST. Eur J Clin Invest 2011; 41(12): 1339-1352

Αναδιαμόρφωση του τοιχώματος των αεραγωγών Βρογχικός βλεννογόνος φυσιολογικού ατόμου και ασθενούς με βρογχικό άσθμα (Ε-Ηx40), Busse W, Lemanske RF. NEJM 2001; 344:350-362 1. Υπερπλασία καλυκοειδών κυττάρων, 2. Πάχυνση της υποβλεννογόνιας μεμβράνης και εναπόθεση κολλαγόνου, 3. Κυτταρική διήθηση της υποβλεννογόνιας στοιβάδας, 4. Πάχυνση των λείων μυϊκών ινών, επίταση της αγγείωσης

Φλεγμονή και αναδιαμόρφωση των αεραγωγών στο βρογχικό άσθμα Holgate ST, Polosa R. Lancet 2006; 368:780-793

Since the 1980s, the explosive increase in knowledge of the mechanisms of asthma has only led to modest improvements in therapy Asthma is a complex disorder made up of different subtypes with differing causes, treatment responses and natural histories Holgate ST. Eur J Clin Invest 2011; 41(12): 1339-1352

Almost since the inception of the concept that immunity can be divided into TH1 and TH2 type processes, asthma has been considered a TH2 process

Linear representation of the Th2-inflammation hypothesis

Eur Respir J 1999; 14: 1210-1227

Numerous environmental factors can influence an underlying immunoinflammatory process. Obesity

TH2 associated asthma Th2 associated asthma is linked strongly to atopy and allergy, eosinophilic inflammation and response to corticosteroids Atopy: a genetically mediated predisposition to an excessive IgE reaction Allergy: a hypersensitivity disorder of the immune system Allergy is one of four forms of hypersensitivity and is formally called type I In type 1 hypersensitivity reaction, an antigen is presented to CD4+ Th2 cells specific to the antigen that stimulate B-cell production of IgE antibodies also specific to the antigen that activate mast cells and basophils

The innate immune system: first line of defense, Φυσική ανοσία Αναγνώριση παθογόνων με συγκεκριμένα μοριακά πρότυπα (PAMP) μέσω ειδικών υποδοχέων (PRR) (TLR) Anatomical barrier Skin Gastrointestinal tract Respiratory airways and lungs Nasopharynx Eyes Additional defense mechanisms Sweat, desquamation, flushing organic acids Peristalsis, gastric acid, bile acids, digestive enzyme, flushing, thiocyanate, defensins, gut flora Mucociliary elevator, surfactant defensins Mucus, saliva, lysozyme Tears

The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogen growth. Επίκτητη ανοσία: Εγκατάσταση ανοσολογικής μνήμης

TCD4+ lymphocytes, or helper T cells, are immune response mediators: establish and maximize the capabilities of the adaptive immune response Th1 cells are defined by the production of IFN-g and orchestrate protection from intracellular pathogens; Th2 cells are characterized by the production of IL-4, IL-5, and IL-13 and mediate protection from extracellular parasites Th17 cells are distinguished by their production of IL-17 and IL-22 and are believed to be involved in the clearance of extracellular bacteria and fungi

TH2 immune processes in the airways of people with asthma. Wenzel SE. Nature Med 2012; 18(5): 716-725

Primary sensitization of the airways in the induction of allergic-type asthma

Airway remodeling in the epithelial mesenchymal trophic unit.

The diversity of microbial exposure is inversely related to the risk of asthma. It is still unclear whether airway inflammation is primarily caused by the presence of allergens and infectious pathogens or primarily caused by the absence of a natural microbiological environment.

Questioning the Th2-inflammation hypothesis existing T-cell immunosuppressives and new Th2-targeted treatments have no or marginal effectiveness in the clinic substantial residual disease remains when anti-inflammatory therapy is optimized some patients have severe asthma. Moreover, the Th2-inflammation model cannot account for the substantial clinical and molecular heterogeneity that has now been unequivocally documented in human asthma.

Άσθμα από το Α στο Β Am J Respir Crit Care Med 2009; 180: 388-395

periostin (POSTN), chloride channel regulator 1 (CLCA1), and serpin peptidase inhibitor,clade B, member 2 (SERPINB2): epithelial genes specifically induced in asthma a gene signature for Th2-driven inflammation in airway epithelial cells is prominent in only half of patients with asthma; non Th2-driven mechanisms therefore operate in the remaining half.

a significant percentage of patients with asthma have a Th2-low phenotype that manifests clinical features of asthma, airway obstruction, airway hyperresponsiveness, and bronchodilator reversibility despite a paucity of Th2-driven inflammation. The causes of Th2-low asthma remain obscure, but possibilities include neutrophilic inflammation, IL-17 driven inflammation, intrinsic defects in barrier function and chronic subclinical infection by viruses, and atypical intracellular bacteria.

Theoretical range of factors that may be involved in the development of non-th2 asthma.

Neutrophilic inflammation in an endobronchial biopsy from a patient with severe asthma Wenzel SE. Lancet 2006; 368:804-813

The pleiotropic effects of Treg cells in suppressing allergic inflammatory pathways.

PGE2 is widely regarded as the prostranoid possessing the most prominent immunomodulatory, antifibrotic and bronchodilating properties Meanwhile, CysLT include LTC4, LTD4, and LTE4 mediates airway smooth muscle contraction, mucus hypersecretion, microvascular permeability, and airway edema Clin Rev Allergy Immunol 2012 Nov (ahead of print)

Open framework asthma endotype model

Airway hyperresponsiveness (AHR), easily triggered bronchospasm, is the most characteristic clinical feature of asthma. Chronic airway inflammation is currently considered to be the key trigger of AHR in asthma. However, AHR can persist in the absence of inflammation due to persistent functional changes in effector cells of AHR (such as neurons and smooth muscle cells) and structural changes in the airways.

Bara I, et al. ERJ 2010; 36:1174-1184

Mechanisms of asthmatic bronchial smooth muscle (BSM) remodelling.

Allergy 2012; 67(3):396-402

Impaired ASM cell calcium homeostasis leading to enhanced proliferation in asthma and altered cell contractility

Mast cell myositis in asthma

Nat Med 2012; 18(5): 716

Failure to recognize and discover the underlying mechanisms of these major variants or endotypes of asthma Is the major intellectual limitation to progress at present. Lancet 2008; 372: 1107-1119

Σας ευχαριστώ πολύ