The feedback loop breaking simulations are consistent with the in silico knockout experiments in this study, together identifying the network inflammatory determinants for CODP progression. For example, IL-6 is not only a product from Loop 1, but also a key component of both Loops 2 and 4. IL-6 is an important proinflammatory factor for synthesis of acute phase proteins such as C-reactive protein, which is associated with several acute and chronic inflammatory diseases including COPD [15, 73, 74]. This cytokine is also identified as a major regulator of the balance between Treg and Th17 (CD8+T) cells as seen in our above discussions. As IL-6 plays an important role in COPD progression, it has recently been recognized as a potential target for COPD [73, 74]. Another example is that IL-17 as well as Th-17 is identified as a key component for COPD. Targeting IL-17 and Th-17 has become a promising strategy for treatment of the disease . However, COPD is a complex and heterogeneous disorder, e.g. similar clinical phenotypes can come from different endotypes, which are associated with different molecular and cellular mechanisms, as shown in our above modeling analysis. It is critical to identify the molecular and cellular disease mechanisms, by which subtypes of COPD patients are defined. As such, future treatment options would target the identified endotypes using available anti-inflammatory drugs . For this purpose, specific biomarkers of these endotypes would be particularly useful. Our modeling study offers a possible approach to probe endotype biomarkers for COPD and provides novel insight into this personalized medicine strategy as discussed above.