Determining the Role of GPX, an antixodant, in the Inflammatory Changes Associated with Emphysema

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Determining the Role of GPX, an antixodant, in
the Inflammatory Changes Associated with Emphysema

• Navida Bholanauth
• Dr. Jeanine DArmiento
• Columbia University

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Emphysema

• Definition Pathological disease characterized
  by the abnormal enlargement of the distal
  airspaces of the lung.
• Cigarette smoking is the major factor associated
  with development of emphysema.
• Age Adjusted Mortality for COPD has increased by
  71 between 1966 and 1995.
• 24 million Americans affected with 119,000 deaths
  annually.
• 32.1 billion dollars in costs annually in this
  country.

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Oxidants and COPD

• Each puff of smoke contain 1014 free radicals
• Free radicals cause direct damage to lipids,
  proteins and DNA
• Oxidants induce lung epithelial cells to release
  cytokines IL-1, IL-8 and TNF-a
• Induce influx of inflammatory cells
• Hypothesis An oxidant/antioxidant imbalance can
  lead to the development of emphysema

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Some Common Sources of Antioxidants

• Vitamin E
• Vitamin C
• Selenium

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Antioxidants and Lung

• Rich network of antioxidants to protect the lung
• Antioxidants are increased in response to
  cigarette smoke
• Antioxidant responses are quite variable
• Differences in antioxidant responses may account
  for differences in disease susceptibility
• Epidemiologic data links antioxidants to COPD
  symptoms and disease severity (MORGEN Study).

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Antioxidants and the Lung
Kinnula, AJRCCM 2003
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Experimental Protocol

• Mice that expressed human GPX1 were bred on a
  C57xCBA background
• Gene was under control of the mouse HMG CoA
  reductase promoter
• The activity of the enzyme was increased 3.9 fold
  in the lungs of transgenic mice
• Transgenic and littermate control mice were
  exposed to chronic cigarette smoke
• Comparative analyses were made with non-exposed
  transgenic and control mice.

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Research Aims

• Determine the effect of GPX1 expression on the
  induction of inflammation by cigarette smoke.
• Evaluate the effect of GPX1 on smoke-mediated
  emphysema formation.

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Glutathione Peroxidase-1 Decreases Smoke Induced
Macrophage Influx
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Glutathione Peroxidase-1 Decreases Smoke Induced
Neutrophil Influx
Wild-type GPX SM
SM
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(No Transcript)
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GPX1 Prevents Cigarette Smoke-Induced Emphysema
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Summary of Findings

• GPX1 expression in the lung prevented the
  inflammatory response to cigarette smoke
  exposure.
• The expression of GPX1 protected against the
  development of smoke-induced emphysema.
• The major research goals are to determine the how
  GPX1 expression regulates smoke-induced
  inflammation.

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Oxidant Signaling and Inflammatory Cell
Recruitment

• MAPK signaling
• -T cell differentiation and activation
• -induction of cellular adhesion molecules and
  chemokines
• -p38 inhibition decreased neutrophilia in
  response to cigarette smoke exposure
• NF-kB
• -regulates the expression of pro inflammatory
  genes

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Smoke-Derived Oxidants and MAPK Activation
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Smoke-Derived Oxidants and NF-?B Activation
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Chronic Effects of Cigarette Smoke on MAPK
Activation
p-JNK
p38
p-ERK
Actin
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Chronic Effects of GPX1 and Cigarette Smoke on
NF-?B Activation
_____________ control
_____________ control
_____________ smoke-exposed
_____________ smoke-exposed
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Results

• Lungs of GPX mice have less emphysematous changes
  than wildtype smoke exposed mice.
• Inflammatory markers, macrophages and
  neutrophils, are decreased in the lungs of GPX
  mice as compared to wildtype smoke exposed mice.
• P-JNK and P-38 seem to be regulated with smoke
  exposure.
• GPX as compared to WT have less p-38 and p-JNK at
  baseline and increase with smoke exposure but
  less than wildtype smoke exposed mice.
• There is no regulation of I?B with smoke exposure
  in wildtype mice and less for GPX baseline and
  smoke exposed mice.

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Conclusions

• Smoke exposed GPX mice seem to display less
  emphysematous changes in than smoke exposed
  wildtype mice.
• There is a marked decrease in inflammation in GPX
  mice after smoke exposure.
• Though there seems to be regulation with p38 and
  pJNK, further studies need to be done to see why
  GPX mice have less baseline levels of these
  markers and what that means during smoke
  exposure.

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MentorJeanine DArmiento

• Robert Foronjy
• Vincent Lemaitre
• Tina Zelonina
• Jincy Thankachen
• Alison Wallace
• Mark Maxfield
• Divya Mehra
• David Sternberg
• Polina Golovach
• Summer Students Leslie, Nakisha Enoelia

• Collaborators
• Oleg Mirochnitchenko
• Olga Propokenko
• Yasunori Okada
• Masayori Inouye
• Kazushi Imai

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References

• Author name et al. Year. Name of Journal
  (abbreviation at bottom).