Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder characterized by progressive destruction of lung tissues and airway obstruction. COPD is currently the third leading cause of death worldwide and there is no curative treatment available so far. Cigarette smoke (CS) is the major risk factor for COPD. Yet, only a relatively small percentage of smokers develop the disease, showing that disease susceptibility varies significantly among smokers. As smoking cessation can prevent the disease in some smokers, quitting smoking cannot halt the progression of COPD in others. Despite extensive research efforts, cellular and molecular mechanisms of COPD remain elusive. In particular, the disease susceptibility and smoking cessation effects are poorly understood. To address these issues in this work, we develop a multiscale network model that consists of nodes, which represent molecular mediators, immune cells and lung tissues, and edges describing the interactions between the nodes. Our model study identifies several positive feedback loops and network elements playing a determinant role in the CS-induced immune response and COPD progression. The results are in agreement with clinic and laboratory measurements, offering novel insight into the cellular and molecular mechanisms of COPD. The study in this work also provides a rationale for targeted therapy and personalized medicine for the disease in future.

Fig 1. Network model for CS-induced immune response.

Interactions between various nodes that represent cytokines, immune cells, and TD are described (for detailed description, see text).

Fig 2. CS-induced (S = 1.67) population dynamics.

M₁, M₂ and D_C of dynamics over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].

Fig 3. CS-induced (S = 1.67) population dynamics.

Dynamics of I_α, I₆, I₁₀, I_β, I_γ, I₁₇ and I₄ over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].

Fig 4. CS-induced (S = 1.67) population dynamics.

Dynamics of (a)T₈, T_g, T₁₇, T₂, and T₁, and (b) T_D.

Fig 5. CS-induced (S = 0.7) population dynamics.

Dynamics of M₁, M₂ and D_C over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].

Fig 6. CS-induced (S = 0.7) population dynamics.

Dynamics of I_α, I₆, I₁₀, I_β, I_γ, I₁₇ and I₄ over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].

Fig 7. CS-induced (S = 0.7) population dynamics.

Dynamics of (a) T₈, T_g, T₁₇, T₂, and T₁, and (b) T_D.

Fig 8. Effects of cigarette smoking cessation on T_D dynamics.

Smoking cessation occurs after t = 400, 800, 900, 1500, and 2500 days of CS exposure, respectively.

Fig 9. Dynamics of T_D with different values of k₁₃ and effects of cigarette smoking cessation.

(a) k₁₃< 2.6×10⁻² ml/(cell day) corresponds to resistant smokers (T_D<30%), while k₁₃≥2.6×10⁻² ml/(cell day) is associated with susceptible smokers. (b) Effects of smoking cessation after 2500 days of CS exposure. 2.6×10^-2ml/(cell day) ≤ k₁₃ < 0.31ml/(cell day) corresponds to reversible susceptible smokers and COPD is reversible. k₁₃≥0.31 ml/(cell day) is associated with severely susceptible smokers. In this case, COPD is not reversible.

Fig 10. In silico knockout simulations.

(a) T_D dynamics, (b) I_α dynamics, (c) I₆ dynamics, and (d) I₁₇ dynamics. In silico knockouts of M1 (red dashed line), DC (red circles), Th1 (black stars), Th17 (black plus), CD8⁺T (black squares), TNF-α (blue dash-and-dot line), INF-γ (black asterisk), IL-6 (blue triangles), and IL-17 (black cross) [wild type is denoted by WT (black solid line)].

Fig 11. Loop breaking simulations.

Loops 1, 2, 3, and 4 are broken on TD→M1 (blue line), TD→IL-6 (red line), M1→IL-12 (cyan line), and IL-6 ┫Treg (pink line), respectively (WT denotes wild type in black line) for dynamics of T_D.

Fig 12. One of Loops 1, 2, 3, and 4 is activated while the others are broken.

(a) Loop 1, 2, or 4 alone causes CODP while Loop 3 does not. (b) As Loop 1 is activated, M₁ (red solid line) predominates over M₂ (red dashed line). While Loop 4 is activated, both M₁ (blue solid line) and M₂ (blue dashed line) are relatively low. (c) In the case where Loop 1 is activated, T_g is predominant over T₈ or T₁₇. (d) The activation of Loop 4 leads to the predominance of T₈ and T₁₇ over T_g.