**5.1 Cigarette smoke induced inflammation**

Cigarette smoke initiates inflammation both by direct oxidative-irritative cellular injury and indirectly by recruiting several inflammatory cells in the air space(ATS,1962,Barnes et al.,2008;Shapiro & Ingenito,2005 as cited in Shapiro SD,2010). Neutrophils rapidly accumulate in the lung in response to exposure to cigarette smoke(Rennard,2003 as cited in Shapiro SD,2010). Recruitment occurs via stimulated epithelial cells and macrophages releasing TNF-α and neutrophil chemokines CXCL1 and CXCL8 (IL-8) operating through the neutrophil receptor CXCR2(Barnes,2008 as cited in Shapiro SD,2010). Neutrophils contain proteinases like neutrophil esterase(NE) and Matix metalloproteinases(MMPs), particularly MMP-9, which are preformed and stored in granules and readily released upon activation. In addition to causing matrix destruction, proteinases generate fragments of ECM proteins such as collagen and laminin, which are also chemotactic for neutrophils, leading to a vicious feedback cycle of inflammation and tissue destruction(Adair-Kirk et al.,2003;Gaggar et al.,2008;Mydel et al.,2008 as cited in Shapiro SD,2010).

COPD is characterized by a gradual, progressive accumulation of macrophages in the lung most apparent in respiratory bronchioles which is the primary site of centriacinar emphysema(Niewoehner et al.,1974 as cited in Shapiro SD,2010). Stimulated macrophages produce both neutrophil and macrophage chemokine and cytokines like macrophage chemotactic protein-1 (MCP-1; CCL2), which recruits more monocytes from the peripheral blood(Barnes,2008 as cited in Shapiro SD,2010).Macrophages produce a variety of MMPs,

They result from overdistention and rupture of alveoli during birth, or as sequelae of pneumonia and other infections. They have been observed in tuberculosis lesions during

It results from any process that allows free air to enter into the subcutaneous tissue. It can also result from pneumomediastinum or pneumothorax,fracture of the orbit, following tracheotomy, perforation in the esophagus or laryngopharyngeal area. Rarely, air is formed

The etiopathogenesis of COPD involves interplay of several over-lapping and co-existing injuries, defects, inflammation and disorganized repair in a vicious cycle, ultimately leading to a chronic progressive impairment of lung function. These processes are shared by other airway and parenchymal diseases of lungs and aggravated by other pulmonary and systemic co-morbidities. The key steps involved are epithelial injury, inflammatory cell activation, protease-antiprotease imbalance, airway inflammation, goblet cell hypertrophy and hypersecretion, recurrent infection, acute exacerbations, attempts to disorganized repair and fibrosis, ultimately leading to chronic progressive permanent airway obstruction(Barnes,2008;Kasahara & Tuder,2000;MacNee & Tuder,2009;Rennard,2003 as

Cigarette smoke initiates inflammation both by direct oxidative-irritative cellular injury and indirectly by recruiting several inflammatory cells in the air space(ATS,1962,Barnes et al.,2008;Shapiro & Ingenito,2005 as cited in Shapiro SD,2010). Neutrophils rapidly accumulate in the lung in response to exposure to cigarette smoke(Rennard,2003 as cited in Shapiro SD,2010). Recruitment occurs via stimulated epithelial cells and macrophages releasing TNF-α and neutrophil chemokines CXCL1 and CXCL8 (IL-8) operating through the neutrophil receptor CXCR2(Barnes,2008 as cited in Shapiro SD,2010). Neutrophils contain proteinases like neutrophil esterase(NE) and Matix metalloproteinases(MMPs), particularly MMP-9, which are preformed and stored in granules and readily released upon activation. In addition to causing matrix destruction, proteinases generate fragments of ECM proteins such as collagen and laminin, which are also chemotactic for neutrophils, leading to a vicious feedback cycle of inflammation and tissue destruction(Adair-Kirk et

COPD is characterized by a gradual, progressive accumulation of macrophages in the lung most apparent in respiratory bronchioles which is the primary site of centriacinar emphysema(Niewoehner et al.,1974 as cited in Shapiro SD,2010). Stimulated macrophages produce both neutrophil and macrophage chemokine and cytokines like macrophage chemotactic protein-1 (MCP-1; CCL2), which recruits more monocytes from the peripheral blood(Barnes,2008 as cited in Shapiro SD,2010).Macrophages produce a variety of MMPs,

al.,2003;Gaggar et al.,2008;Mydel et al.,2008 as cited in Shapiro SD,2010).

**4.4.6 Bullous emphysematous blebs or cysts (pneumatoceles)** 

in the subcutaneous tissues by gas-producing bacteria.

specific antibacterial therapy.

**5. Etiopathogenesis** 

cited in Shapiro SD,2010).

**5.1 Cigarette smoke induced inflammation** 

**4.4.7 Subcutaneous emphysema** 

particularly elastases such as MMP-9 and MMP-12, resulting in lung tissue injury. Degraded elastin fragments are chemotactic for macrophages, thus ensuing a self-propagating cycle(Houghton et al.,2006;Senior et al.,1980 as cited in Shapiro SD,2010).

T cells lympocytes, especially CD8+ cells are increased in airway walls and alveoli of patients with COPD(Saetta et al.,1998 as cited in Shapiro SD,2010). Airway epithelial cells in smokers with COPD have increased expression of CXCL10 (IP-10), the ligand for CXCR3 found on CD8+Tcells and thus may be the activation pathway for macrophages to produce MMP-12(Grumelli et al.,2004;Saetta et al.,2002 as cited in Shapiro SD,2010). Cytotoxic T cells may target epithelial cells and induce cell death, particularly those with (latent) viral infection.

Elastin fragments can serve as autoantigens and immunoglobulin G (IgG) autoantibodies with avidity for pulmonary epithelium have been found in patients with COPD(Feghali-Bostwick et al.,2008;Lee et al.,2007 as cited in Shapiro SD,2010). Increased numbers of B cells and lymphoid follicles in the lung have raised interest in a possible autoimmune pathogenesis of COPD(Curtis et al.,2007;Taraseviciene-Stewart & Voelkel,2008 as cited in Shapiro SD,2010). Interplay of all these inflammatory pathways results in the tissue damage that keeps adding up over the years.
