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Stem Cell Therapy for ARDS

Stem Cell Therapy for ARDS. 顏至慶 指導教授：陳全木教授 中興大學生命科學系 中國醫藥大學附設醫院. Contents. Introduction Acute respiratory distress syndrome (ARDS) Stem cells and plasticity Stem cell Tx in other systems Stem cell Tx for ARDS Stem cells in lung parenchyma Our recent report & Important reports

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Stem Cell Therapy for ARDS

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  1. Stem Cell Therapy for ARDS 顏至慶 指導教授：陳全木教授 中興大學生命科學系 中國醫藥大學附設醫院

  2. Contents Introduction Acute respiratory distress syndrome (ARDS) Stem cells and plasticity Stem cell Tx in other systems Stem cell Tx for ARDS Stem cells in lung parenchyma Our recent report & Important reports Mechanisms of stem cell Tx Conclusions

  3. Introduction - ARDS - Stem Cells & Plasticity

  4. Berlin Definition of ARDS (No ALI) (JAMA 2012; 307:2526-33)

  5. Trend of Incidence of ARDS • 58/100000 per year in USA (2005) • Declining (2001-2008) • perhaps due to: • Lung protective ventilation • Reduction of nosocomial Inf • Conservative use of blood products (NEJM 2005; 353: 1685-93; AJRCCM 2011; 183:59-66)

  6. Trend of Mortality of ARDS • Mortality: 36-44% up to 2006 • Declining (1997-2009) • Perhaps due to • Lung protective ventilation • Supportive Tx: Early antibiotics, Ulcer prevention, Better fluid Tx, Nutritional & organ support (J Clin Invest 2012; 122:2731-40; Postgrad Med J 2011; 87:612-22)

  7. Management for ARDS • Early recognition and avoidance of risk factors • Initial intervention • Lung protective ventilation • Conservative fluid management • Tx for life-threatening hypoxemia => check Pplat • Pplat < 30 => Recruitment and/or High PEEP alone • Pplat > 30 => Prone position or HFV • No improvement => Inhaled NO ? • Low dose steroid after evaluation • ECMO (Crit Care Med 2010; 38:1644-1650)

  8. Directions of Tx. for ARDS • Treat underlying diseases • Inhibition of inflammation • Provide adequate oxygenation • Lung Protective Ventilatory Strategies • Hemodynamic support • Adequate general supportive Tx: • Infection control, Early enteral nutrition, Stress ulcer prophylaxis • Speed lung healing Stem Cells

  9. Stem Cells Stem Cells: limitless self-renewal and differentiation, multipotent Transit Amplifying Cells: proliferation but not self-renewal Maturing Cells: full expression of differentiation markers, no self-renewal, no proliferation (Fuchs E, 2000)

  10. Hematopoietic & MesenchymalStem Cells (MSCs) (Stem Cell Information of NIH)

  11. Plasticity of Adult Stem Cells (Yen, et al. Eur J Clin Invest 2006; 36: 310)

  12. Yamanaka 山中伸彌 教授 (京都大學, 2006) Oct3/4, Sox2, Klf4, c-Myc by retrovirus

  13. Stem Cell Tx in Other Systems

  14. BMCs Improved LVEF – Meta-Analysis (Circulation 2012; 126: 551)

  15. (Circulation 2012; 126: 551)

  16. Stem Cells Tx for ARDS - Stem Cells in Lung Parenchyma - Our recent report - Important reports

  17. Previous Concept of Alveolar Cells ( Circa, 1980 )

  18. New Concept of Lung Stem Cells Endogenous SC Pool Exogenous SC Pool ?(Krause) ?(Kotton) ( Uhal BD, 1997 ) (Yen, et al. Eur J Clin Invest 2006; 36: 310)

  19. Our Recent Report- Amniotic Fluid Stem Cells (AFSCs) from EGFP Transgenic Mice Attenuate Hyperoxia-Induced Acute Lung Injury(PLOS One 2013)

  20. Myofibrobalsts Adipocytes Osteocytes

  21. AFSCs improved survivalBetter than BM-MSC & embryonic fibroblast cells

  22. AFSCs Attenuate Lung Injury

  23. AFSCs reduced acute inflammation and apoptosis

  24. AFSCs reduced inflammatory cytokines (7th days) Immunomodulatory effects of MSCs have been proved

  25. D1 D3 D7 Accumulation of AFSCs within the injured lung Greatest on day 1 Gradually decreased on the following days

  26. Medium from hyperoxic lung increased AFSCs migration

  27. Stem Cell Tx for ARDS (review articles) Critical Care 2012, 16: 205 Current Opinion of Critical Care 2014, 20: 122-131

  28. Key Points • Mesenchymal stem cells, bone marrow-derived mononuclear cells, endothelial progenitor cells, and embryonic or induced pluripotent stem cells => promise for ARDS. • Mechanisms: • Paracrine (antimicrobial and repair factors, KGF) • Cell–cell contact (transfer of nucleic acids and organelles => modulate immune cells) • Engraftment & differentiation • Mesenchymal stem cells: rapidly advanced to clinical testing, with two early phase clinical trials

  29. Recent Reports of Stem Cell TX for ARDS

  30. Intratracheal Tx with MSC Improved Survival in The LPS Model of ALI (Chest 2010; 138:965-972)

  31. Clinical Trial of MSCs for ARDS – 12 patients

  32. MSCs Tx is Safe & Feasible (Respiratory Research 2014, 15:39)

  33. Mechanisms of Stem Cell Therapy

  34. Homing & Migration: Tissue- committed CXCR4 Cells Attracted by SDF-1 + Others (Ratajczak, 2004; Feng et al., 2012)

  35. Mechanisms of Stem Cell Tx (Curr Opin Crit Care 2014,20:122-131)

  36. (Curr Opin Crit Care 2014,20:122-131)

  37. Conclusions - Stem Cell Therapy (Yen, et al. Eur J Clin Invest 2006; 36: 310)

  38. 謝謝聆聽　敬請賜教

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