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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.


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).
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pone.0163192.g001: 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).

Mentions: In the present network model shown in Fig 1, M1, DC, Th1, CD8+T and Th17 cells along with their corresponding cytokines, TNF-α, IL-6, IL-12, IFN-γ, and IL-17 form multiple proinflammatory pathways, whereas M2, Th2 and Treg cells with the associated cytokines, IL-4, TGF-β, and IL-10, form anti-inflammatory/regulatory pathways. The inflammatory and anti-inflammatory/regulatory pathways are interlinked with each other through several nodes representing molecular mediators such as IL-6, TGF-β and IL-10 (Fig 1). These pathways eventually converge at the TD node that represents the tissue damage. Here, we focus on the immunologic aspects of COPD and the TD node is highly coarse-grained, involving neutrophil-induced tissue damage, epithelial and endothelial cell injury and extracellular matrix degradation etc. As discussed above, for example, M1 produces chemokines to recruit neutrophils (not shown in Fig 1) for the release of neutrophil elastase and ROS, contributing to TD. The representation of this process is included indirectly in the M1→TD motif shown in Fig 1. In addition, while M1 secretes MMPs to cause TD, TD also produces EFs to recruit monocytes for generating M1. This process is represented in the M1→TD→M1 positive feedback loop where MMPs and EFs are included indirectly (Fig 1). As TD is the major feature of CODP in the lung parenchyma, the dynamics of TD is used to characterize the progression of COPD in this work.


Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling
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).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0163192.g001: 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).
Mentions: In the present network model shown in Fig 1, M1, DC, Th1, CD8+T and Th17 cells along with their corresponding cytokines, TNF-α, IL-6, IL-12, IFN-γ, and IL-17 form multiple proinflammatory pathways, whereas M2, Th2 and Treg cells with the associated cytokines, IL-4, TGF-β, and IL-10, form anti-inflammatory/regulatory pathways. The inflammatory and anti-inflammatory/regulatory pathways are interlinked with each other through several nodes representing molecular mediators such as IL-6, TGF-β and IL-10 (Fig 1). These pathways eventually converge at the TD node that represents the tissue damage. Here, we focus on the immunologic aspects of COPD and the TD node is highly coarse-grained, involving neutrophil-induced tissue damage, epithelial and endothelial cell injury and extracellular matrix degradation etc. As discussed above, for example, M1 produces chemokines to recruit neutrophils (not shown in Fig 1) for the release of neutrophil elastase and ROS, contributing to TD. The representation of this process is included indirectly in the M1→TD motif shown in Fig 1. In addition, while M1 secretes MMPs to cause TD, TD also produces EFs to recruit monocytes for generating M1. This process is represented in the M1→TD→M1 positive feedback loop where MMPs and EFs are included indirectly (Fig 1). As TD is the major feature of CODP in the lung parenchyma, the dynamics of TD is used to characterize the progression of COPD in this work.

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.