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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


CS-induced (S = 1.67) population dynamics.Dynamics of Iα, I6, I10, Iβ, Iγ, I17 and I4 over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5036797&req=5

pone.0163192.g003: CS-induced (S = 1.67) population dynamics.Dynamics of Iα, I6, I10, Iβ, Iγ, I17 and I4 over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].

Mentions: 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 [47]) (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].


Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling
CS-induced (S = 1.67) population dynamics.Dynamics of Iα, I6, I10, Iβ, Iγ, I17 and I4 over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036797&req=5

pone.0163192.g003: CS-induced (S = 1.67) population dynamics.Dynamics of Iα, I6, I10, Iβ, Iγ, I17 and I4 over a time period of (a) 4000 days and (b) 180 days [the dashed square region in (a)].
Mentions: 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 [47]) (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].

View Article: PubMed Central - PubMed

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.

No MeSH data available.