To investigate the importance of the positive feedback loops shown in Fig 1 in COPD progression, a feedback loop breaking approach is applied in the present study. Here, four aforementioned positive feedback loops, M1→TD→M1 (Loop 1), IL-6→Th17→ IL-17→TD→IL-6 (Loop 2), M1→IL-12→Th1→IFN-γ→M1 (Loop 3), and IL-6 ┫Treg→IL-10 ┫Th17→IL-17→TD→IL-6 (Loop 4), are explored by setting, e.g., k3 in Eq (A), kI6, TD in Eq (J), and kI12, M1 in S1 File to zero, leading to the breaking of Loops 1–3 on TD→M1, TD→IL-6, and M1→IL-12, respectively. We set KTg, I6 in Eq 6 to a very large value, e.g., 104 to break Loop 4 on IL-6 ┫Treg in the calculation. Simulations were performed using our model with the parameters in Table A in S1 File (dTD = 2.9×10−3/day). The results reveal that breaking Loop 1, 2, or 4 allows TD to remain less than 10% (Fig 11), indicating that COPD does not occur. However, breaking Loop 3 has no profound effects on COPD progression (cyan line in Fig 11). This finding is consistent with virtual knockout of Th1 discussed above.