maria nilda m. muñoz, msc associate professor of medicine ... · associate professor of medicine...

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 ……


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 !


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


COPD risk is related to the total burden

of inhaled particles.

Aging

Populations


• 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.


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.


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


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.


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.


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.


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.


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


Full response

Non-responseSevere

adverse

reactionPartial-response

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,


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


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

mailto:[email protected]

maria nilda m. muñoz, msc associate professor of medicine ... · associate professor of medicine...

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