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CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ZULEYHA OZEN. OVERVIEW. Introduction Information about Chronic Obstructive Pulmonary Disease (COPD ) Inflammatory Responses Paper 1 Paper 2 What is still unknown? Future Studies/Specific Aim. Disease Overview.

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overview
OVERVIEW
  • Introduction
  • Information about Chronic Obstructive Pulmonary Disease (COPD)
  • Inflammatory Responses
  • Paper 1
  • Paper 2
  • What is still unknown?
  • Future Studies/Specific Aim
disease overview
Disease Overview
  • Pathophysiology of COPD(Chronic Bronchitis and Emphysema)

-Chronic Bronchitis: Loss of muco-ciliary clearance

  • Loss of cilia function

-Emphysema: Destruction of elastin fibers

  • Proteases, matrix metalloproteinase 9 (MMP9) cause elastin degradation

Shortness of Breath

Cough/Sputum-(Progressive dyspnea)

http://www.wgabinecie.pl/artykul/65-pochp-przewlekla-obturacyjna-choroba-pluc/

current existing medicines
Current existing medicines

Bronchodilators

Combination of Bronchodilators and cortisteroids

Vaccines

Pulmonary Rehabilitation

Oxygen Therapy

Change in Lifestyle

slide5

http://www.ncbi.nlm.nih.gov/books/NBK26827/figure/A4531/?report=objectonlyhttp://www.ncbi.nlm.nih.gov/books/NBK26827/figure/A4531/?report=objectonly

https://www.caymanchem.com/app/template/Article.vm/article/2177

inflammatory and immune cells involved in chronic obstructive pulmonary disease copd
Inflammatory and immune cells involved in chronic obstructive pulmonary disease (COPD)

Macrophages and epithelial cells:

-chemotactic factors

-attract inflammatory cells

http://www.nature.com/nri/journal/v8/n3/fig_tab/nri2254_F2.html

t h 17 cells and airway inflammation
 TH17 cells and airway inflammation

http://www.nature.com/nri/journal/v8/n3/fig_tab/nri2254_F5.html

smoke exposure n 20 group whole body exposed to cigarette smoke cs
Smoke Exposure (n=20/group)Whole body exposed to cigarette smoke (CS)

20 mice exposed to CS of 5 cigarettes

20 mice exposed to CS of 5 cigarettes

20 mice exposed to CS of 5 cigarettes

20 mice exposed to CS of 5 cigarettes

30 min

smoke free interval

30 min smoke-free interval

30 min smoke-free interval

The CS exposure animals were divided into two subgroups:

Control group: exposed to air

Sub-acute exposure:

Initiated CS at 26-28 weeks old

Chronic exposure: initiated CS at 6-8 weeks old

Mice of each group 30-32 weeks old when the CS & Air exposure ended

figure 1 assessing effect of cs exposure on lung inflammation
Figure 1. Assessing effect of CS exposure on lung inflammation
  • Total number of alveolar inflammatory cells increased in chronic CS exposure
  • Sub-acute exposure significantly lower than chronic CS
slide11

Figure 2A. Prevalence of Th17 cells in lung tissue

Prevalence of Th17 cells:

-ratio of CD4+ IL-17A+ cells to the total amount of CD4+ T lymphocytes

-Th17 prevalence markedly higher in mice with chronic CS and Sub-acute CS

slide12

Figure 2B. Peripheral blood mononuclear cells

-similarly the prevalence of Th17 cells increased in CS exposure

Figure 2C. Collective analysis of flow cytometry

slide13
Figure 3A. Prevalence of T regulatory cells (ratio of CD4+CD25+Foxp3+ cells to the total amount of CD4+ T lymphocytes) in lung tissue

Prevalence of T regulatory cells:

-markedly higher in sub-acute exposure

-drops in chronic CS exposure

slide14
Figure 3B. Peripheral blood mononuclear cells-similarly the prevalence of T regulatory cells decreased in chronic CS exposure

Figure 3C. Collective analysis of flow cytometry

figure 4 assessing the ratio of th17 and treg in lung tissue and peripheral blood
Figure 4. Assessing the ratio of Th17 and Treg in lung tissue and peripheral blood

-In lung tissues, the ratio of Th/Treg is decreased with sub-acute CS exposure

-Increases in chronic CS exposure

Ratio of Th17/Tregin peripheral blood:

-significantly increased in chronic CS exposure

figure 5 the expression of foxp3 and ror gamma t mrna
Figure 5. The expression of Foxp3 and ROR gamma t mRNA

-Looking at specific transcription factors of both T-subsets by real time-PCR

-Th17 specific transcription factor ROR gamma t mRNA expression: significantly increased in CS exposed

-T regulatory specific transcription factor Foxp3 mRNA expression: significantly decreased in CS exposed

slide17

Table 1: levels of IL-17A, IL-6, IL-23 and TGF-beta in serum significantly higher in chronic CS exposure

-IL-10 sig. lower in chronic CS

conclusions from paper 1
Conclusions from paper 1
  • There is an obvious imbalance between Th/Treg cells in CS exposed mice
  • Prevalence of Th17 and Th17 specific transcription factor, ROR gamma t mRNA: increased
  • Treg cell prevalence and Treg specific transcription factor, Foxp3 mRNA: decreased
    • Thus, leading to an imbalance in the ratio of Th/Treg cell profiles
  • The existing cytokine profile can be further evaluated for specific therapeutic approach
figure 1 a ssessing histology of lung tissues
Figure 1. Assessing histology of lung tissues

Fig.1 Histology of Lung Tissues

  • Mean alveoli were expanded and broken
  • COPD lung- more inflammatory cells
figure 2 expression of transcription factors ror gamma t and foxp3
Figure 2. Expression of transcription factors ROR gamma t and Foxp3
  • Fig.2a. Foxp3 relative mRNA expression level significantly lower in COPD patients
  • Fig.2b. RORyt relative mRNA expression level significantly higher in COPD patients
  • Fig.2c. Ratio of Treg/Thelper cells in the level of mRNA lower in COPD patients
slide22

Figure 3. Assessing expression of Foxp3 and ROR gamma t protein levels

-Increased protein expression of ROR gamma t in COPD patients

-Viceversa, decreased protein expression of Foxp3 compared with smokers and nonsmokers

figure 4 immuno histochemistry staining of different proteins
Figure 4. Immunohistochemistry staining of different proteins

All p-values were less than 0.001

-IL-17+, CCR6+ and IL-23R cells increased

-Foxp3 cells in alveolar walls decreased

figure 5 the number of foxp3 il 17 ccr6 and il 23r cells in alveolar walls
Figure 5. The number of Foxp3+, IL-17+, CCR6+ and IL-23R+ cells in alveolar walls

-Foxp3+ and Foxp3+ / IL-17+ cells decreased in cell number in chronic CS exposure

-IL-17+, CCR6+ and IL-23R+ cells increased in cell number in chronic CS exposure

  • -Foxp3+ & Foxp3+/IL-17+ cells decreased in alveolar walls of COPD
slide25

A: ROR gamma t & Foxp3 mRNA expression: negatively correlated

B: Ratio of Foxp3/ROR gamma t mRNA expression negatively correlated with mean alveoli area

C: Positive correlation with the ratio of Foxp3/ROR gamma t and FEV1%pred

slide26

D: ROR gamma t & Foxp3 protein: negatively correlated

E: Ratio of Foxp3/ROR gamma t in level of protein and mean alveoli area

F: Positive correlation with the ratio of Foxp3/ROR gamma t in level of protein and FEV1%pred

slide27

G: Numbers of Foxp3+/IL-17+ cells: negatively correlated

H: Ratio of Foxp3/IL-17+ cells: negatively correlated to the mean alveoli area

I: Positive correlation with the ratio of Foxp3+/IL-17+ cells and FEV1%pred

conclusions from paper 2
Conclusions from paper 2
  • Decreased ratio of Foxp3/ROR gamma t in patients with COPD and normal smokers
    • persistent with the aggravation of the disease
  • Decreased ratio of Foxp3/ROR gamma t important in pathogenesis of COPD
    • Immune dysregulation, and participation in lung inflammation: leading to destruction in the lung
    • Pro-inflammatory cytokines and chemokine receptors are also evident in development of the disease
    • Their association with the transcription factors ROR gamma t and Foxp3 can be further researched for potential therapeutics
what is still unknown
What is still unknown ?

The regulatory cytokine involvement: TGF-beta levels in the progression of the disease is still unknown

Study by Zhou et al. TGF-beta induced Foxp3 leads to inhibition of Th17 cell differentiation

In a dose dependent matter, TGF-beta might be a factor seen in the imbalance between Th/T regulatory cells

Specific Aim

  • In the research proposal, my area of focus will be to further analyze the negatively correlated relationship between the T-regulatory and T helper cells with regards to changes in the expression of the specific transcription factors and cytokine TGF-beta
  • Implement TGF-beta induced Foxp3 and use of cytokine IL-6 antagonist for therapeutic approach