Maria Nilda M. Muñoz, MScAssociate Professor of Medicine &Director, Research Management Office
St. Luke’s College of Medicine, WHQM, Quezon City
St. Luke’s College of Medicine
concerns itself with understanding the
interactions between the various systems of
a cell, including the interactions between the
different types of DNA, RNA and protein
biosynthesis as well as learning how these
interactions are regulated.
Molecular ……
St. Luke’s College of Medicine
COPD in 2014
COPD International
Your International Support Network
http://www.copd-international.com/
We can learn to control this disease,
instead of letting COPD controls us !
St. Luke’s College of Medicine
The Dutch Hypothesis:
• Asthma and COPD are the same disease “the same bird with different feathers
The British Hypothesis:
• COPD is due to chronic infection , completely different from asthma
The American Hypothesis:
• COPD is due to direct toxic effect of cigarette smoke
St. Luke’s College of Medicine
COPD risk is related to the total burden
of inhaled particles.
Aging
Populations
St. Luke’s College of Medicine
• Protease/antiprotease
• TNF-α gene polymorphisms
• Microsomal epoxide hydrolase*
• Glutathione S-transferase P1
• Transforming growth factor beta 1*
• Metalloproteinase dysregulation
– Hersh, CP et al. Genetic association analysis of functional
impairment in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2006; 173: 977-984.
St. Luke’s College of Medicine
Protease/Anti-protease
• Alpha –1- antitrypsin/elastase imbalance.
• Alveolar macrophages from COPD patients express more matrix metalloproteinase (MMP)-9 than normals. Elevated MMP-9 is associated with an increase in degradation of elastin.
Russell RE et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2002;283:L867-L873.
St. Luke’s College of Medicine
May influence host immune responses, increase inflammatory tissue damage, and favor the development of chronic bronchitis- a specific TNF-a polymorphism found in 19% CB vs. 5% schoolchildren vs. 2% of controls
Huang SL et al. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 1997; 156:1436
St. Luke’s College of Medicine
Microsomal epoxide hydrolase
• Microsomal epoxide hydrolase (MEH) reduces
highly reactive epoxide intermediates generated by
smoking. The genotypes associated with decreased
activity of MEH were found in 19 and 22 per cent of
COPD patients vs. 6% controls– Smith CAD, Harrison DJ. Association between polymorphism in gene for
microsomal epoxide hydrolase and susceptibility to emphysema. Lancet
1997; 350:630.
St. Luke’s College of Medicine
Glutathione S-transferase P1
• Glutathione S-transferase P1 aids in the
detoxification of substances in cigarette smoke, and
COPD may occur more frequently among persons
with decreased activity of this enzyme by virtue of
genetic polymorphisms.
– Ishii, T et al. Glutathione S-transferase P1 polymorphism in
patients with chronic obstructive pulmonary disease. Thorax 1999;
54:693.
St. Luke’s College of Medicine
TGFβ1
• TGF-β1 is a member of a large family of polypeptides involved in cellular growth, differentiation, and activation. Specific, single nucleotide polymorphisms of the gene encoding TGF-β1 have been associated with the development of COPD in smokers.
– Wu, L et al. Transforming growth factor beta1 genotype and susceptibility to chronic obstructive pulmonary disease. Thorax 2004; 59:126.
St. Luke’s College of Medicine
St. Luke’s College of Medicine
Systemic Inflammation in
Pathogenesis of COPD• COPD is a systemic disease.
• Cytokines and other inflammatory markers are a response to cigarette smoke.
• They circulate and may impact other diseases and symptoms, e.g. cardiac disease and cachexia.
• Reduced lung function associated with increased levels of systemic inflammatory markers, including CRP, fibrinogen, WBC’s, and TNF-alpha.*
Gan WQ et al. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and meta-analysis.
Thorax 2004; 59:574.
St. Luke’s College of Medicine
St. Luke’s College of Medicine
St. Luke’s College of Medicine
TIOTROPIUM – a long-acting parasympatholytic agent
and its precursor, IPROTROPIUM
Inhaled STEROID: mainstay for therapy in both asthma and COPD
THEOPHYLLINE: therapeutically applicable to both asthma and COPD
Leukotriene-modifying drugs: used occasionally for COPD
St. Luke’s College of Medicine
Full response
Non-responseSevere
adverse
reactionPartial-response
St. Luke’s College of Medicine
St. Luke’s College of Medicine
St. Luke’s College of Medicine
Muñoz NM, Kim KP, Han SK, Boetticher E, Sperling AI, Sano H, Zhu X, Cho W, Leff AR. Characterization of monoclonal antibodies specific for 14 kDa human group V secretory phospholipase A2 (hVPLA2). Hybridoma 19: 171–176, 2000
Muñoz NM, Kim YJ, Meliton AY, Kim KP, Han SK, Boetticher E, O'Leary E, Myou S, Zhu X, Bonventre JV, Leff AR, Cho W. Human group V phospholipase A2 induces group IVA phospholipase A2-independent cysteinyl leukotriene synthesis in human eosinophils. J Biol Chem 278: 38813–38820, 2003.
Muñoz NM, Meliton AY, Arm JP, Bonventre JV, Cho W, Leff AR. Deletion of secretory group V phospholipase A2 attenuates cell migration and airway hyperresponsiveness in immunosensitized mice. J Immunol 179: 4800–4807, 2007.
Muñoz NM, Meliton AY, Lambertino A, Boetticher E, Learoyd J, Sultan F, Zhu X, Cho W, Leff AR. Transcellular secretion of group V phospholipase A2 from epithelium induces β2-integrin-mediated adhesion and synthesis of leukotriene C4 in eosinophils. J Immunol 177: 574–582, 2006.
Kim YJ, Kim KP, Han SK, Muñoz NM, Zhu X, Sano H, Leff AR, Cho W. 2002. Group V phospholipase A2 induces leukotriene biosynthesis in human neutrophils through the activation of group IVA phospholipase A2. J Biol Chem 277: 36479–36488,
St. Luke’s College of Medicine
Am J Physiol Lung Cell Mol Physiol. 2013Mechanical induction of group V phospholipase A(2) causes lung inflammation and acute lung injury.Meliton AY1, Muñoz NM, Meliton LN, Birukova AA, Leff AR, Birukov KG.
CHEMOKINES
CYTOKINESLIPID MEDIATORS
EPI/ENDO
MAST CELLS
MACROPHAGES
SMOOTH MUSCLE
PMNs/EOS, Tcells
1. Humanized Group V PLA2: regulatory role in asthma and COPD
2. EFFECTIVITY OF MEDICINAL PLANTS IN LUNG INFLAMMATION,
METABOLIC DISORDER, PAIN MANAGEMENT, RA, ETC.
3. DENGUE RESEARCH: SIGNAL TRANSDUCTION
4. AIR-TRAFFIC POLLUTANTS IN LUNG DISEASES
5. ANIMAL MODEL OF DISEASES
St. Luke’s College of Medicine
Maria Nilda M. Muñoz, MSc
Director, Research Management Office and
Associate Professor of Medicine
5th Floor, Research Management Office
Sta. Ignaciana St., Cathedral Heights
St. Luke’s College of Medicine, WHQM
Quezon City
Email: [email protected]
Contact #: 723-0101 local 3507