The network model in this paper involves multiple immune cells, cytokines and lung tissues, forming multiple proinflammatory and anti-inflammatory/regulatory pathways with several positive feedback loops. The in silico knockout experiments performed in this study have identified several important proinflammatory elements including IL-6, IL-17 cytokines, and M1, DC, Th17, CD8+T cells. It is intriguing to note that despite high concentrations of TNF-α often found in COPD smokers, our present study shows that this cytokine may not play a significant role in the progression of COPD. This finding is consistent with biopharmaceutic and clinical studies [6, 18, 19]. The feedback loop breaking simulations demonstrate that Loops 1, 2 and 4, which all involve the TD node, play important but different roles in the COPD progression. Activation of Loop 1, which enhances the M1 and TD productions, can promote the M1/M2-type COPD while Loops 2 and 4 contribute to the (Th17+CD8+T)/Treg-type disease where IL-6 and IL-17 are key molecules for the disease progression. These results indicate that COPD can be heterogeneous and can result from different molecular and cellular mechanisms.