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01.MPG THESIS.Pdf UNIVERSITY OF BARCELONA Faculty of Medicine Department of Physiological Sciences I TIME COURSE OF BIOCHEMICAL, BIOMECHANICAL AND HISTOLOGICAL CHANGES FOR THE ASSESSMENT OF INFLAMMATION AND REMODELLING IN A BLEOMYCIN-INDUCED MURINE MODEL OF LUNG INJURY DISSERTATION submitted in partial fulfilment of the requirements for the degree of DOCTOR OF PHILOSOPHY by Mariona Pinart Gilberga Supervisors: Dr. Pablo V. Romero Colomer (Bellvitge Hospital) Dr. Patricia Rieken Macedo Rocco (Federal University of Rio de Janeiro) Tutor: Dr. Daniel Navajas “Biopathology in medicine” doctorate program (2004-2006) The author of this thesis has been supported by grants from: • Fundació August Pi i Sunyer - Red RESPIRA (03/RED-020), Spain (Year 2004); • Institut d’Investigacions Biomèdiques de Bellvitge (06/IDB-001) during the years 2005-2007. The studies have been funded by: • Red Respira (ISCiii RTIC 03/011), Spain (Year 2004); • Fondo de Investigaciones Sanitarias (FISS) grant PI 04/0671, Ministerio de Sanidad, Spain (Year 2004); • Centres of Excellence Program (PRONEX-FAPERJ), Brazilian Council for Scientific and Technological Development (CNPq), Carlos Chagas Filho, Rio de Janeiro State Research Supporting Foundation (FAPERJ), Brazil (Year 2005). "Quando o homem aprender a respeitar o menor ser da Criação, seja animal ou vegetal, ninguém precisará ensiná-lo a amar seu semelhante" Albert Schurveitzer To the people I love Index INDEX ABBREVIATIONS............................................................................................. III I. INTRODUCTION............................................................................................. 1 I.1. MECHANISMS OF LUNG TISSUE REPAIR: SEQUENCE OF EVENTS OCCURING DURING WOUND HEALING...................................................... 3 I.1.1. Injury: initial triggering events............................................................. 5 I.1.2. Inflammatory events........................................................................... 7 I.1.3. Reparative processes: remodelling and resolution/fibrosis .............. 10 I.2. REGULATION OF LUNG MATRIX REMODELLING .............................. 14 I.2.1. The role of the fibroblasts................................................................. 14 I.2.2. The role of the alveolar epithelium in fibrogenesis ........................... 16 I.2.3. Epithelial cells and fibroblasts: structural repair and remodelling in the airways...................................................................................................... 18 I.2. 3.1. The role of TGFβ in lung disease................................................... 20 I.2.3.1.1. The role of other cytokines using the TGFβ pathway .................. 21 I.3. EXTRACELLULAR MATRIX................................................................... 23 I.3.1. Changes of the extracellular matrix induced by the inflammatory- remodelling process .................................................................................. 23 I.3.1.1. Collagen....................................................................................... 25 I.3.1.2. Elastic fibres ................................................................................. 26 I.3.1.3. Matrix metalloproteinases.......................................................... 28 I.3.2. Oxidative stress (myeloperoxidase) ................................................. 30 I.3.3 Pulmonary fibrosis............................................................................. 32 I.3.3.1 Definitions and classification....................................................... 32 I.3.3.2 Pathogenesis................................................................................. 34 I.4. LUNG BIOMECHANICS ......................................................................... 34 I.4.1. Physiology of the lung ...................................................................... 34 I.4.2. Lung structure .................................................................................. 35 I.4.3. Concepts of mechanical parametres................................................ 36 I.4.3.1. Resistance ................................................................................... 36 I.4.3.2. Elastance and compliance ............................................................. 36 I.4.3.3. Hysteresivity ................................................................................. 37 I.4.4. Measurements of lung tissue mechanics ......................................... 38 I.4.5. Mechanical forces in pulmonary fibrosis........................................... 42 I.5. ANIMAL MODELS OF LUNG INJURY.................................................... 44 I.5.1. Objectives ........................................................................................ 44 I.5.2. Advantages and disadvantages of animal models ........................... 44 I.5.3. Animal models for the development of pulmonary fibrosis ............... 45 I.5.3.1. Bleomycin molecule ...................................................................... 46 I.5.3.2. Bleomycin-induced lung injury model .............................................. 47 I.5.3.3. Mechanisms of bleomycin-induced lung damage.............................. 49 II. HYPOTHESIS OF THE THESIS AND OBJECTIVES.................................. 53 II.1 HYPOTHESIS OF THE THESIS............................................................. 55 II.2 OBJECTIVES ......................................................................................... 56 III. STUDY DESIGN ......................................................................................... 57 i Index III.1. BLEOMYCIN-INDUCED MURINE MODEL .......................................... 59 III.1.1. Animals .......................................................................................... 59 III.1.2. Anaesthesia and analgesia ............................................................ 59 III.1.3. Experimental model........................................................................ 60 III.1.4. Biomechanical analysis .................................................................. 62 III.1.5. Statistical analysis.......................................................................... 66 III.2. PARAMETRES STUDIED IN LUNG PARENCHYMA........................... 67 III.2.1. Myeloperoxidase ............................................................................ 67 III.2.2. Hydroxyproline ............................................................................... 67 III.3. HISTOLOGY......................................................................................... 68 III.3.1. Morphometry .................................................................................. 68 III.3.2. Collagen fibres ............................................................................... 69 III.3.3. Elastic fibres................................................................................... 69 III.3.3.1. Protocol of dehydration of lung tissue strips ................................... 69 III.3.3.2. Sample staining .......................................................................... 69 III.3.3.3. Quantification of elastic fibres ....................................................... 70 IV. RESULTS ................................................................................................... 71 IV.1 OBJECTIVES 1 AND 2................................................................................ 73 IV.1 OBJECTIVES 3 AND 4................................................................................ 83 V. DISCUSSION............................................................................................... 91 V.1 MECHANICAL BEHAVIOUR IN RATS INTRATRACHEALLY INSTILLED WITH BLM: A TWO-WEEK MODEL OF BLM.............................................................................. 93 V.2 MECHANICAL BEHAVIOUR IN RATS INTRATRACHEALLY INSTILLED WITH BLM: A COMPARISON BETWEEN A FOUR-WEEK SINGLE DOSE MODEL AND A FOUR-WEEK AFTER THREE REPEATED DOSES ....................................................................... 96 V.3 STRENGTHS AND WEAKNESSES OF THE BLM MODEL.................................... 99 VI. FINAL CONCLUSIONS............................................................................ 103 VII. REFERENCES ........................................................................................ 107 VIII. ANNEX ................................................................................................... 145 ii Abbreviations ABBREVIATIONS η hysteresivity Ψ Young elastic modulus AECs alveolar epithelial cells ARDS acute respiratory distress syndrome AT-1 type-1 pneumocytes cells AT-2 type-2 pneumocytes cells BAL bronchoalveolar lavage BLM bleomycin E elastance ECM extracellular matrix EGF epidermal growth factor EMT epithelial-mesenchymal transition FGF fibroblast growth factor G tissue damping H elastic modulus HP hidroxyproline i.p intraperitoneal i.v intravenous IL interleukins IIP idiopathic interstitial pneumonias IPF idiopathic pulmonary fibrosis LI lung index MMPs matrix metalloproteinases MPO myeloperoxidase NGF nerve growth factor PARP poly-(ADP-ribose) polymerase PDGF platelet-derived growth factor PF pulmonary fibrosis PGE prostaglandin PMN polymorphonuclear leukocytes R resistance RD repeat dose RNS reactive nitrogen species iii Abbreviations ROS reactive oxygen species s.c subcutaneous SD single dose TGF transforming growth factor TIMPs tissue inhibitors of metalloproteinases TNF tumor necrosis factor
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