As shown in Fig 2(B), M1 along with Iα and I6 [Fig 3(B)] rises to a peak at 12 days of CS exposure and then decays until day 60 because of the suppression of IL-10 secreted mainly by M2, showing an acute inflammatory response to the CS exposure. These results are qualitatively consistent with experiments in mice ) (see Figure B in S1 File for comparison with mice experiments). This period of time can be referred as step 1 in the progression of COPD as proposed by Agusti et al. [2–3]. After step 1, however, the inhibitory effect of IL-10 on M1 (as well as proinflammatory cytokines) is counteracted by the production of M1 up-regulated by TNF-α, TD, and INF-γ (Fig 1). It turns out that M1 is increased (but slowly) up to day 180 [Fig 2(B)]. This time period is referred as step 2 in the COPD progression [2, 3]. During this period, DC along with I12 (data not shown), I6 and Iβ [Fig 3(B)], and I21 (data not shown) increases slowly and gradually, resulting in the slow productions of T1, T17, and T8, respectively. Consequently, TD rises gradually during this period. After step 2, innate proinflammatory network elements start to go up quickly as M1 predominates over M2 again [Fig 2(A)]. In particular, I6 is increased more rapidly than Iα [Fig 3(A)], enhancing the production of T17 and T8 and allowing the adaptive immunity to play an increasingly important role in response to the CS exposure and in tissue damage (Fig 4). Notably, T8 goes up more quickly than T1 and T17 [Fig 4(A)], dominating in the late phase in the COPD progression. Eventually, TD together with the immune cells and cytokines goes to a steady state (stable COPD) as shown in Fig 4(B). The results for the above immune cells and cytokines at the steady state are listed in Table B in S1 File. Our results are in agreement with experiments [55–63].