MECHANISMS AND OUTCOMES OF PULMONARY MECHANICAL STRESS Walter A. Zin, MD, DSc firstname.lastname@example.org Laboratory of Respiration Physiology Carlos Chagas Filho Institute of Biophysics Federal University of Rio de Janeiro
Airways Lung parenchyma Vascular system Abnormal physical forces Pathological Situations Variety of physical forces SDRA VILI Introduction • The lung is a dynamic organ
Fluid layer Shear stress Epithelial cells Basement membrane Stretch Mechanical Stimuli in The Lung • The types of physical forces also differ depending on the part of the cell where they are acting
Mechanical Stimulus • Imprecise terms: • Stretch • Distension • Accurate definitions: • Stress • Strain Proliferation Differentiation Gene expression Synthesis and secretion of protein Stress Cell or Strain Structure Function Metabolism Pattern Degree
Tensile stress Compressive stress Shear stress Mechanical Stimulus • Definitions: • Stress –force per unit area acting on a plane within a body • ‘Shear stress’ – forces are parallel to the plane • ‘Compressive stress’ – stress is directed toward the part on it acts • ‘Tensile stress’ – stress is directed away from the part on which it acts Roark RJ (1954). Formulas for Stress and Strain. McGraw-Hill Book Company, New York.
Mechanical Stimulus • Definitions (continued): • Strain – any forced change in length in relation to the initial length • ‘Tensile Strain’ – stretch • ‘Compressive Strain’ – shortening • ‘Shear Strain’–an angular distortion Roark RJ (1954). Formulas for Stress and Strain. McGraw-Hill Book Company, New York.
Mechanical Stress in The Lung • Shear stress • Mainly occurs in: • Conducting airways (airflow) • Vascular system (blood flow) • Also occurs in: • Pleural mesothelial cells (pleural fluid) • Airway and alveolar epithelial cells (fluid layer) Schumacker PT (2002) Am J Physiol Lung Cell Mol Physiol 282: L881-L882
Shear Stress: Fluid Layer Schurch S et al. (2001) Comp Biochem Physiol A: Mol Integr Physiol 129: 195-207
Mechanical Stress in The Lung • ARDS & VILI • Edema fluid shearing forces alveoli • Repetitive opening and collapse of distal lung units high shear stress • Mechanical ventilation • Elevated airflows also increase the shear stress parallel to the surface of the airways and alveolar walls Wirtz HR, Dobbs LG (2000). Respir Physiol 119: 1-17 Kotani M, Kotani T, Li Z, et al. (2004) Eur Respir J 24: 238-246 Nucci G, Suki B, Lutchen K (2003) J Appl Physiol 95: 348-356
Mechanical Ventilation Dreyfuss D, Saumon G (1998) Am J Respir Crit Care Med 157: 294-323
Mechanical Ventilation: Inflammation Knight PR & Rotta A (2005) Acute Lung Injury: Etiology and Basic Features. In: Lung Injury. Notter RH, Finkelstein JN, Holm BA, eds.
Mechanical Strain in The Lung • Strain • More prominent in cells of alveolar epithelium during breathing • ARDS: heterogeneity of alveolar ventilation bigger mechanical strain increased cell distortion • Endothelium is also subjected to strain • During lung inflation: • Extra-alveolar vessels – tensile strain (interdependence) • Alveolar vessels – compressive strain • Cytoskeletal rearrangements Schumacker PT (2002) Am J Physiol Lung Cell Mol Physiol 282: L881-L882 Wirtz HR, Dobbs LG (2000). Respir Physiol 119: 1-17
Integrin receptor Stretch-sensitive ion channels Growth factor receptor Focal Adhesion Complex Nucleus Mechanosensors • Common mechanosensors include: Ingber DE (1997). Annu Rev Physiol 59: 575-599 Chiquet M (1999). Matrix Biol 18: 417:426
Mechanical stimuli Mechanosensors • Generation of second-messenger molecules • Activation of specific protein kinases • Phosphorylation and activation of participating signalling molecules • Amplification through enzymatic cascades • Modulation of gene expression Nucleus Mechanosensors • Mechanosensors subsequently activate and interplay various intracellular events
Mechanical stimuli Not well understood Biochemical and biomolecular changes Gene expression Putative Mechanisms for Mechanotransduction • Mecanotransduction = the conversion of mechanical stimuli into intracellular biochemical and biomolecular alteration
Mechanical stimuli Intracellular events c-fos, c-jun, c-myc, JE, EST-like protein (ELK)-1, activation protein (AP)-1, specificity protein (SP)-1, nuclear factor (NF)-B, Early growth response (Egr)-1 Proteins related to transcriptional factors Signal transduction Putative Mechanisms for Mechanotransduction • In the nucleus, physical forces can exert their effects by influencing expression of immediate early genes, which encode proteins related to transcriptional factors and signal transduction Komuro I, et al. (1991). J Biol Chem 266: 1265-1268
Mechanotransduction: Shear Stress (vessels) Lehoux S & Tedgui A (2006) In: Ventilator-Induced Lung Injury. Dreyfuss D, Saumon G, Hubmayr RD, eds.
Mechanotransduction: Transmural Pressure Lehoux S & Tedgui A (2006) In: Ventilator-Induced Lung Injury. Dreyfuss D, Saumon G, Hubmayr RD, eds.
Mechanotransduction: Mechanically Activated Ion Channels Pathway Parker JC, Miyahara T, Anghelescu M (2006) In: Ventilator-Induced Lung Injury. Dreyfuss D, Saumon G, Hubmayr RD, eds.
Mechanotransductions: Plasma Membrane Stress Disruption Pathway Dos Santos CC & Slutsky AS (2000). J Appl Physiol 89: 1645-1655
Soluble factors Soluble factors Soluble factors Intercellular junctions Nucleus Nucleus Cell-matrix interaction Cell-Cell Interaction Correa-Meyer E, et al. (2002). Am J Physiol Lung Cell Mol Physiol 282: L883-L891 Tschumperlin DJ, et al. (2002) Am J Physiol Lung Cell Mol Physiol 282: L904-L911
1. Direct inflammatory paradigm Mediators Cytokines Growth factors Infiltration of the airway wall with inflammatory cells Remodeled airway wall Events initialing inflammation Mediators Cytokines Growth factors 2. Mechanotransduction paradigm Mechano-transduction by airway epithelial cells Enhanced airway obstruction Buckling of the airway epithelium Inflammatory and Mechanical Stimuli Tschumperlin DJ & Drazen JM (2001). Am J Respir Crit Care Med 164: 590-594
Mechanical Force-Induced Production of Inflammatory Mediators • Inflammatory response: • Seems to depend on the type of injurious stimulus • Follows different molecular pathways • Is characterized by: • Cytokines release • Seems to depend on the magnitude of cyclic strain on alveolar cells and/or the association of a subjacent inflammatory injury; • Even interventions of very short duration such as recruitment manoeuvres could be potentially dangerous. • Prostaglandin synthesis Ricard JD, et al. (2001) Am J Respir Crit Care Med 163: 1176-1180 Copland IB, et al. (2003) Am J Respir Crit Care Med 168: 1051-1059
Inflammation: Pollution Costa DL (2005) Inhalation Toxicology: Methods and Models. In:Lung Injury. Notter RH, Finkelstein JN, Holm BA, eds.
Control Morphology Paraquat: Injection 24 h prior to the experiment 10 mg/kg 15 mg/kg 25 mg/kg 30 mg/kg Rocco PRM et al (2001)Am J Respir Crit Care Med 164: 1067-1071
Pollution: Extracelular Matrix Paraquat: Injection 24 h prior to the experiment Rocco PRM et al (2001)Am J Respir Crit Care Med 164: 1067-1071
Mechanical Ventilation: Inflammation Goodman RB et al (2003) Cytokine Growth Factor Rev 14: 523-535
Mechanical Ventilation: Inflammation Dos Santos CC & Slutsky AS (2005) Ventilation Therapies and Strategies for Acute Lung Injury. In: Lung Injury. Notter RH, Finkelstein JN, Holm BA, eds.
POSITIVE END-EXPIRATORY PRESSURE PREVENTSLUNG MECHANICALSTRESS CAUSED BYRECRUITMENT/DERECRUITMENT Control groups(CTRL), rats with mechanical atelectasis (ATEL), and rats with acute lung injuryinduced by paraquat (ALI). The animals from each group were non-recruited but ventilatedfor 1 hour in ZEEP (ZEEP), or submitted to recruitment maneuvers and ventilated for 1hour in ZEEP (RM-ZEEP) or PEEP (RM-PEEP). J Appl Physiol. 2005 Jan;98:53-61.
1h PCIII/GAPDHratio as a function of amplitude, at 1 Hz under a force of 0.5 x 10−2 N. PCIII/GAPDH ratio as a function of force, at 1 Hz and with 5% LB. WHAT INCREASES TYPE III PROCOLLAGEN mRNA LEVELS IN LUNG TISSUE:STRESS INDUCED BY CHANGES IN FORCE OR AMPLITUDE? 1h Respir Physiol Neurobiol. 2004;144:59-70
WHAT INCREASES TYPE III PROCOLLAGEN mRNA LEVELS IN LUNG TISSUE:STRESS INDUCED BY CHANGES IN FORCE OR AMPLITUDE? The stress induced by changes in amplitudehad a smaller coefficient of correlation than thestress induced by force Respir Physiol Neurobiol. 2004;144:59-70