Folie 1

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Institute and Outpatient Clinic for Occupational
and Environmental Medicine Ziemssenstrasse 1
80336 Munich Germany http//arbmed.klinikum.uni-
muenchen.de
Lung injury and repair induced by chemicals
Dennis Nowak, Rudolf Jörres
Institute and Outpatient Clnic for Occupational
and Environmental Medicine Ludwig-Maximilians-Univ
ersität München Germany
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Inhalation injury Definition

• Effect of acture exposure to high concentrations
  of toxic (and asphyxiating) gases and aerosols

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Lung injury and repair induced by chemicals

• Agents and mechanisms
• Experimental example ozone
• Experimental data repair

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Chemical agents causing pulmonary injury Gases
Acetaldehyde Strong oxidizer, upper airway
irritant, delayed ARDS Acrolein Oxidizer, upper
airway irritant, delayed ARDS Ammonia Alkali,
water soluble, upper airway irritant Boranes Wate
r-insoluble, upper airway irritant Chlorine Inter
mediate solubility, upper and lower airway
irritant Hydrogen chloride Water soluble, upper
airway irritant Hydrogen fluoride Irritating
odor,upper airway irritant, ARDS Isocyanates Reac
tive chemical, irritant, airway
reactivity Lithium hydride Odorless, strong
oxidizer, upper airway irritant Oxide of nitrogen
(NO, NO2, N2O4) Water insoluble, pneumonitis,
ARDS, bronchiolitis oblit. Ozone Water
insoluble, pneumonitis, ?ARDS Phosgene Water
insoluble, pneumonitis, ARDS Sulfur
dioxide Water soluble, pneumonitis, ARDS,
bronchiolitis oblit.
Schwartz DA, in D. Hendrick et al., 2002
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Chemical agents causing pulmonary injury Metals
Antimony Oxidizer, upper airway
irritant Cadmium Odorless, pneumonitis,
ARDS Cobalt Oxidizer, irritant,
dyspnea Manganese Oxidizer, metal fume
fever Mercury Odorless, pneumonitis,
ARDS Nickel Musty odor, asthma,
pneumonitis Zinc White aerosol, upper airway
irritant, metal fume fever
Schwartz DA, in D. Hendrick et al., 2002
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Water solubility and mechanisms of injury
Gas Solubility Mechanism of injury Ammonia Hig
h Alkali burns Chlorine Intermediate Acid
burns, reactive oxygen species Hydrogen
chloride High Acid burns Oxides of
nitrogen Low Acid burns, reactive oxygen
species Ozone Low Reactive oxygen
species Phosgene Low Acid burns Sulfur
dioxide High Acid burns
Schwartz DA, in D. Hendrick et al., 2002
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Inhalation injury Determinants

• Diameter? 10 µm ? upper
  airwayslt 5 µm ? ? distal
  airways, alveoli
• Water solubilityhigh ?
  upper airwayslow ?
  alveoli
• Dose
• pHacid ? ?
  coagulationalkali ? colliquation

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Inhalation injury Mechanisms
1. Acute toxic bronchitis, tracheitis 2.
Bronchoconstriction 3. Bronchiolitis
obliterans 4. Alveolar damage 5. Pulmonary
edema 6. Asphyxia
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Mechanisms 1. Acute toxic bronchitis, tracheitis
Mainly due to highly water soluble
agents Retrosternal pain, cough Frequently with
conjunctivitis, rhinorrhea, hoarseness,
aphonia Reflex inhibition of deep
breathing Neutrophilia, bronchitis, epithelial
permeability ?, Mucosal edema, ulceration,
bleeding, necrosis
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Mechanisms 2. Bronchoconstriction
Mainly following exposure to Sulfur dioxide,
sulfuric acid, isocyanates, formaldehyde May be
followed by RADS
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Criteria for the diagnosis of irritant asthma
(Reactive Airways Dysfunction Syndrome) 1.
Absence of preceding respiratory complaints 2.
Onset of symptoms occurring after a single
specific exposure incident or accident 3.
Exposure was to a gas, smoke, fume or vapour that
was present in very high concentrations and
had irritant qualities 4. Onset of symptoms
occuring within 24 hours after the exposure
and persisting for at least three months 5.
Symptoms consistend with asthma, with cough,
wheezing and dyspnoea predominating 6. Pulmonary
function tests may show airflow obstruction 7.
Appropriate challenge testing showing increasing
airway responsiveness 8. Other types of
pulmonary diseases excluded
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Mechanisms 3. Bronchiolitis obliterans
Predominantly following nitrogen dioxide, sulfur
dioxide, ammonia, chlorine Latency period! 3 wks
later sometimes BOOP Severe disease with cough,
dyspnea, fever, restriction, diffusion
impairment, hypoxemia, sometimes peripheral
airway obstruction Histology Corticosteroids
obligatory
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Mechanisms 4. Alveolar damage
Mainly after phosgene and ozone (low
solubility) Particles 0,5 - 3 µm Typ I alveolar
cells particularly sensitive Damage to alveolar
macrophages probably responsible for high number
of subsequent bacterial pneumonias
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Mechanisms 5. Pulmonary edema
Following lipophilic agents such as nitric oxide
and phosgene Seldomly after escessively high
exposure to water soluble agents like
chlorine Severe parenchymal damage Artificial
ventilation with PEEP Pharyngeal edema ?
tracheotomy Case reports Early steroids
advantageous May develop BOOP
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Mechanisms 6. Asphyxia

• Displacement of oxygen
• (CO2, N2, CH4) lt 14 O2 ? Symptoms,
• lt 10 ?
  nausea,
• 
  paroxysms,
• 
  unconsciousness
• Displacement of oxygen from ist hemoglobin
  binding (e.g., CO)
• Blocking of cellular enzymes (HCN, H2S)

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Burn injury Fibreoptic bronchoscopy
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Lung injury and repair induced by chemicals

• Agents and mechanisms
• Experimental example ozone
• Experimental data repair

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Mechanisms of action of inhaled ozone

• penetrates into deeper airways
• maximum retention near terminal bronchioles
• lipid peroxidation
• loss of functional groups of biomolecules
• reactive aldehydes, hydrogen peroxide,hydroxy
  hydroperoxides
• activation of eicosanoid metabolism
• cell activation
• stimulation of nerve endings

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Effects of ozone inhalation in human subjects

• Airway lumen (BALF/sputum)
• Neutrophils
• (Lymphocyte subpopulations)
• mCD14 on macrophages
• phagocytosis
• IL-8, IL-6, GM-CSF
• PGE2, PGF2a, TxB2
• Substance P, bradykinin
• Elastase, MPO
• Total protein, LDH
• Fibronectin, fibrinogen, albumin, IgG
• GSH, GSSG, uric acid, ascorbate
• Malondialdehyde, orthotyrosine
• (Surfactant composition)

• Airway walls
• Neutrophils
• Mast cells
• Endothelial P-selectin, ICAM-1
• (IL-5, GM-CSF, ENA-78, IL-8in asthma)

• Systemic
• Conflicting data

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Ozone Neutrophil influx
12 h after exposure
Hiltermann et al., Clin Science 1995
Fahy et al., Env Research 1995
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Ozone Dose-response of inflammation
Holz et al., AJRCCM 1999
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Inflammatory response to ozone is reproducible
Changes in the proportion of sputum neutrophils
after 250 ppb ozone, 3 h
Consecutive inhalations of saline 1 h after
challenge
3 NaCl
4 NaCl
5 NaCl
Second Exposure
Asthma
Healthy
First Exposure
Holz et al., AJRCCM 1999
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Tolerance to ozone regarding inflammation in
BALF
4 h exposures to 200 ppb ozone
Jörres et al., AJRCCM 2000
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No tolerance to ozone regarding mucosal
inflammation
4 h exposures to 200 ppb ozone
Jörres et al., AJRCCM 2000
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Lung injury and repair induced by chemicals

• Agents and mechanisms
• Experimental example ozone
• Experimental data repair

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Ozone Effect of steroid treatment
(median range)
Nightingale et al., AJRCCM 2000
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Ozone Effect of steroid treatment
Holz et al., J Clin Pharmacol 2005
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Amelioration of ozone-induced lung injury by
anti-tumor necrosis factor-a
BALF albumin
BALF fibronectin
Bhalla et al. 2002
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Amelioration of ozone-induced lung injury by
anti-tumor necrosis factor-a
Relative gene expression in lung tissue assessed
by array
Bhalla et al. 2002
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Attenuation of ozone-induced lung injury by
interleukin-10
IL-10 is an anti-inflammatory cytokine inhibiting
synthesis of TNF-alpha and IL-1 and decreases
expression of iNOS
BALF albumin
BALF fibronectin
Reinhart et al. 1999
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Neutrophils enhance clearance of necrotic
epithelial cells in ozone-induced lung injury in
rhesus monkeys
Number of necrotic epithelial cells per mm2 of
epithelial basal lamina and surface of exposed
basal lamina that is devoid of epithelium
No clearance of cells at 48 h after treatment
with anti-neutrophil antibody (Ab)
Hyde et al. 1999
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Bleomycin induced lung injury
CD 44 is a cell receptor system necessary to
clear hyaluronan fragments after lung injury
Noble PW, D Jiang, PATS 3 (2006) 401-404
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Promising in vitro findings In the future also
in vivo?
Tissue Engineering 11 (2005) 1115-1121
Circulation 111 (2005) 1407-1414
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