**5.2 Proteinase-antiproteinase imbalance**

Elastin and collagen is critical to the structural integrity of the lung. Experimental studies in animal lung models with instilled proteinases have replicated emphysematous changes(Gross et al.,1964 as cited in Shapiro SD,2010) resulting in an initial rapid increase in air space size due to direct elastolysis with diminution of lung elastin content at 24 hours followed by rapid restoration of total lung elastin to normal levels(Janoff et al.,1977;Snider et al.,1984 as cited in Shapiro SD,2010). The anatomic arrangement of the restored elastic fibers is grossly disordered (Kuhn & Senior,1978 as cited in Shapiro SD,2010). The tissue displays inflammation with neutrophils and macrophages with subsequent release of endogenous inflammatory mediators including IL-1β and TNF-α with endogenous proteolytic progression of the disease. Based on these studies and the association between A1PI deficiency with emphysema(Laurell & Eriksson,1963 as cited in Shapiro SD,2010), the proteinase-antiproteinase hypothesis proposed that the balance between matrix-degrading proteinases and their endogenous inhibitors determines whether the lung is protected or susceptible to proteolytic injury.

Some proteinases such as NE and MMP-9 are bound to the surface of the neutrophil, they are resistant to complete inhibition by A1PI and tissue inhibitors of metalloproteinases (TIMPs). "Microenvironmental" concentration of proteinases and their proximity to the target site of matrix proteins when released from the neutrophil and macrophages, may explain how the balance tilts towards the proteinase function even in presence of adequate overall anti-proteinase in circulation(Owen & Campbell,1999 as cited in Shapiro SD,2010). There are four classes of proteinases, serine, cysteine, aspartic, and MMPs:

#### **5.2.1 Serine proteinases**

The serine proteinase Neutrophil elastase(NE) is suspected to be the major causative agent of tissue injury in COPD after the findings that patients deficient in its endogenous

Current Overview of COPD with Special Reference to Emphysema 129

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

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

A1PI , also known as alpha1-antitrypsin, is a serine proteinase inhibitor(serpin) that is produced mainly in the liver and found in the bloodstream and permeates tissues including the lung. A1PI inhibits various serpins including pancreatic trypsin, chymotrypsin but the main target is the neutrophil elastase(Brantly et al,1988;Travis,1989 as cited in Shapiro SD,2010). A1PI is also an acute phase reactant, with its serum concentration rising during pregnancy, during infections, after severe burns, and in the presence of malignant tumors.

A1PI is coded by a single gene with two alleles on chromosome 14q32.1 producing a glycoprotein composed of 394 amino acids. The A1PI gene is highly pleomorphic and more than 75 alleles are known, and they have been classified into normal (normal serum levels and normally functioning A1PI), null (undetectable A1PI in the serum), deficient (serum A1PI levels lower than normal), and dysfunctional (A1PI levels are normal but does not

Most variants of A1PI arise point mutations with a single amino acid substitution. The Z variant(most common and severe disease) results from the substitution of a lysine for a glutamic acid at position 342, which changes the charge and the electrophoretic mobility of the molecule(Yoshida et al,1976 as cited in Shapiro SD,2010). The mutant protein polymerizes and the aggregated form causes hepatic cell injury., The Z protein is also incompletely glycosylated, which may interfere with the protein's excretion from the liver into body fluids. (Ekeowa et al,2009;Gooptu & Lomas,2008 as cited in Shapiro SD,2010). The

al,1991;Swee et al,1995 as cited in Shapiro SD,2010).

**5.5 Alpha-1 protease inhibitor (A1PI) deficiency** 

purely a destructive process but one of aberrant matrix turnover.

Smoking elevates the serum A1PI concentration by about 20%.

function normally)(Brantly et al,1988 as cited in Shapiro SD,2010).

protein looses its physiologic function of inhibiting the NE.

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 leukoprotease inhibitor (SLPI) and elafin.
