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Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease.

Owen CA - Int J Chron Obstruct Pulmon Dis (2008)

Bottom Line: These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung.They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury.In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. cowen@rics.bwh.harvard.edu

ABSTRACT
Since the early 1960s, a compelling body of evidence has accumulated to show that proteinases play critical roles in airspace enlargement in chronic obstructive pulmonary disease (COPD). However, until recently the causative enzymes and their exact roles in pathologic processes in COPD have not been clear. Recent studies of gene-targeted mice in murine models of COPD have confirmed roles for proteinases not only in airspace enlargement, but also in airway pathologies in COPD. These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung. They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury. This review will discuss the biology of proteinases and the mechanisms by which they contribute to the pathogenesis of COPD. In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients.

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Related in: MedlinePlus

Interactions between proteinases regulate inflammation and ECM destruction in mice chronically exposed to cigarette smoke. Neutrophil elastase (NE) promotes inflammation and ECM destruction in mice chronically exposed to cigarette smoke by increasing the influx of PMN and monocytes into the lung (by unknown mechanisms), and by cleaving and inactivating TIMPs to promote MMP-12 mediated ECM degradation. MMP-12 amplifies NE-mediated lung inflammation and destruction by cleaving and inactivating α1-PI, the major inhibitor of NE in the lower respiratory tract. Fragments of elastin generated by MMP-12 (and possibly by NE) amplify MMP-12-mediated lung injury by stimulating the recruitment of blood monocytes into the lung.
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f3-copd-3-253: Interactions between proteinases regulate inflammation and ECM destruction in mice chronically exposed to cigarette smoke. Neutrophil elastase (NE) promotes inflammation and ECM destruction in mice chronically exposed to cigarette smoke by increasing the influx of PMN and monocytes into the lung (by unknown mechanisms), and by cleaving and inactivating TIMPs to promote MMP-12 mediated ECM degradation. MMP-12 amplifies NE-mediated lung inflammation and destruction by cleaving and inactivating α1-PI, the major inhibitor of NE in the lower respiratory tract. Fragments of elastin generated by MMP-12 (and possibly by NE) amplify MMP-12-mediated lung injury by stimulating the recruitment of blood monocytes into the lung.

Mentions: Exposure of WT mice to cigarette smoke for 3–6 months results in airspace enlargement, inflammation, and subepithelial fibrosis in the small airways, similar to that reported in human cigarette smokers (Hautamaki et al 1997; Martin et al 2001). Studies of proteinase-deficient mice in this model have confirmed roles for MMP-12 and NE in regulating chronic lung inflammation and airspace enlargement (Figure 3) and for MMP-9 and/or MMP-12 in inducing subepithelial fibrosis in the small airways of smoke-exposed mice.


Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease.

Owen CA - Int J Chron Obstruct Pulmon Dis (2008)

Interactions between proteinases regulate inflammation and ECM destruction in mice chronically exposed to cigarette smoke. Neutrophil elastase (NE) promotes inflammation and ECM destruction in mice chronically exposed to cigarette smoke by increasing the influx of PMN and monocytes into the lung (by unknown mechanisms), and by cleaving and inactivating TIMPs to promote MMP-12 mediated ECM degradation. MMP-12 amplifies NE-mediated lung inflammation and destruction by cleaving and inactivating α1-PI, the major inhibitor of NE in the lower respiratory tract. Fragments of elastin generated by MMP-12 (and possibly by NE) amplify MMP-12-mediated lung injury by stimulating the recruitment of blood monocytes into the lung.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2629972&req=5

f3-copd-3-253: Interactions between proteinases regulate inflammation and ECM destruction in mice chronically exposed to cigarette smoke. Neutrophil elastase (NE) promotes inflammation and ECM destruction in mice chronically exposed to cigarette smoke by increasing the influx of PMN and monocytes into the lung (by unknown mechanisms), and by cleaving and inactivating TIMPs to promote MMP-12 mediated ECM degradation. MMP-12 amplifies NE-mediated lung inflammation and destruction by cleaving and inactivating α1-PI, the major inhibitor of NE in the lower respiratory tract. Fragments of elastin generated by MMP-12 (and possibly by NE) amplify MMP-12-mediated lung injury by stimulating the recruitment of blood monocytes into the lung.
Mentions: Exposure of WT mice to cigarette smoke for 3–6 months results in airspace enlargement, inflammation, and subepithelial fibrosis in the small airways, similar to that reported in human cigarette smokers (Hautamaki et al 1997; Martin et al 2001). Studies of proteinase-deficient mice in this model have confirmed roles for MMP-12 and NE in regulating chronic lung inflammation and airspace enlargement (Figure 3) and for MMP-9 and/or MMP-12 in inducing subepithelial fibrosis in the small airways of smoke-exposed mice.

Bottom Line: These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung.They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury.In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. cowen@rics.bwh.harvard.edu

ABSTRACT
Since the early 1960s, a compelling body of evidence has accumulated to show that proteinases play critical roles in airspace enlargement in chronic obstructive pulmonary disease (COPD). However, until recently the causative enzymes and their exact roles in pathologic processes in COPD have not been clear. Recent studies of gene-targeted mice in murine models of COPD have confirmed roles for proteinases not only in airspace enlargement, but also in airway pathologies in COPD. These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung. They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury. This review will discuss the biology of proteinases and the mechanisms by which they contribute to the pathogenesis of COPD. In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients.

Show MeSH
Related in: MedlinePlus