**5.2.3 Cysteine proteinases**

Cathepsin L, S, and K are macrophage generated elastolytic enzymes. Cathepsin S also processes antigens in T cells(Riese et al.,1998 as cited in Shapiro SD,2010). Cathepsin K is the most potent elastase and collagenase. Cathepsin B is an epithelial cell product that has proapoptotic properties (Foghsgaard et al.,2001 as cited in Shapiro SD,2010). Cathepsins are inhibited by cystatins like Cystatin C which is the most ubiquitous cystatin found in all human tissues and body fluids. Cathepsins are being studied for their potential to contribute to COPD.

#### **5.3 Cell death**

Cell viability requires cell-matrix attachment via integrins, loss of matrix disrupts the contact and predisposes to cell death (termed "anoikis"). Experimental models show that noninflammatory cell death can initiate air space enlargement as demonstrated in studies involving rodent models with inhibition of vascular endothelial growth factor receptor or instillation of active caspase 3 in lung epithelial cell tissues(Aoshiba et al.,2003;Kasahara & Tuder;2000,Tang et al.,2004 as cited in Shapiro SD,2010). Thus cell death by injury or apoptosis can be an initiating trigger for emphysema.

#### **5.4 Disorganised and incomplete repair**

Injury is followed by aberrant repair of alveolar cells and matrix resulting in coalesced and enlarged air spaces with depleted and disordered parenchymal elastic fibers and excessive,

inhibitor, A1PI, are at increased risk for emphysema and that instillation of NE caused emphysema in experimental models. NE also plays a role in airway disease as a potent secretagogue, facilitator of monocyte transvascular migration. NE is produced mainly by neutrophils, but also to a small degree by monocytes(Shapiro et al.,2003 as cited in Shapiro SD,2010). Cathepsin G (CG) and proteinase 3 (PR3) are other neutrophil-monocyte derived serine proteinases. Other than NE, minor inhibitors are Alpha2 microglobulin, secretory

MMPs are a family of 24 enzymes that require coordination of zinc at the active site, have overlapping substrate specificity, and are inhibited by TIMPs(Parks & Shapiro,2001 as cited in Shapiro SD,2010). Several MMPs degrade elastin and contribute to emphysema including MMP-2, MMP-9 (gelatinase A and B), MMP-7 (matrilysin), and MMP-12 (macrophage elastase). MMP-1, -8, -13 are also collagenases, and thus degrade another critical matrix

Several MMPs have been associated with human COPD including MMP-1, MMP-9, MT1- MMP, and MMP-12(Imai et al.,2001;Molet et al.,2005;Russell et al.,2002 as cited in Shapiro SD,2010). Macrophages have the capacity to produce MMP-1, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-19. MMP-12 is one of the most highly up-regulated genes in macrophages of human smokers(Atkinson & Senior,2003 as cited in Shapiro SD,2010). Role of MMPs in COPD pathogenesis is further supported by the epidemiologic prevalence of polymorphisms of MMP in caucasian COPD patients(Hunninghake et al.,2009 as cited in Shapiro SD,2010).

Cathepsin L, S, and K are macrophage generated elastolytic enzymes. Cathepsin S also processes antigens in T cells(Riese et al.,1998 as cited in Shapiro SD,2010). Cathepsin K is the most potent elastase and collagenase. Cathepsin B is an epithelial cell product that has proapoptotic properties (Foghsgaard et al.,2001 as cited in Shapiro SD,2010). Cathepsins are inhibited by cystatins like Cystatin C which is the most ubiquitous cystatin found in all human tissues and body fluids. Cathepsins are being studied for their potential to contribute

Cell viability requires cell-matrix attachment via integrins, loss of matrix disrupts the contact and predisposes to cell death (termed "anoikis"). Experimental models show that noninflammatory cell death can initiate air space enlargement as demonstrated in studies involving rodent models with inhibition of vascular endothelial growth factor receptor or instillation of active caspase 3 in lung epithelial cell tissues(Aoshiba et al.,2003;Kasahara & Tuder;2000,Tang et al.,2004 as cited in Shapiro SD,2010). Thus cell death by injury or

Injury is followed by aberrant repair of alveolar cells and matrix resulting in coalesced and enlarged air spaces with depleted and disordered parenchymal elastic fibers and excessive,

leukoprotease inhibitor (SLPI) and elafin.

**5.2.2 Matrix metalloproteinases (MMPs)** 

component.

to COPD.

**5.3 Cell death** 

**5.2.3 Cysteine proteinases** 

apoptosis can be an initiating trigger for emphysema.

**5.4 Disorganised and incomplete repair** 

abnormally arranged collagen. Although following pneumonectomy, there is compensatory lung growth of the remaining lung in humans, whether the injured lung can ever reinitiate the process of septation and the intricate juxtaposition of matrix, epithelial, and endothelial cells to form functional alveoli during lung development is highly doubtful(Buhain & Brody,1973;Nolen-Walston et al.,2008;Shifren & Mecham,2006 as cited in Shapiro SD,2010).

Elastin is the principal component of elastic fibers, which allows reversible extensibility and elastic recoil to the intercellular matrix of alveoli throughout the respiratory cycle.Elastin synthesis in the lung begins in the late neonatal period, peaks during early postnatal development, continues to slow through adolescence, and stops by adult life probably because of rapid mRNA degradation preventing expression of the protein.(Shapiro et al,1991;Swee et al,1995 as cited in Shapiro SD,2010).

Animal model studies involving intratracheal injection of elastase show an acute depletion of elastin followed by rapid ECM synthesis, although the lungs develop emphysema(Karlinsky et al.,1983;Kuhn & Senior,1978). The newly synthesized elastic fibers appear disorganized, similar to the elastic fibers in human emphysema and thus emphasizing the role of impaired repair in its pathogenesis. Collagen is the other important ECM fiber to play a role in COPD. Total collagen content in the lung is actually increased in humans with COPD(Wright & Churg,1995 as cited in Shapiro SD,2010). Following tissue injury, excessive collagen deposition around the larger coalesced airspaces is noted. Small airway fibrosis is also prominent in COPD.These findings suggest that emphysema is not purely a destructive process but one of aberrant matrix turnover.
