Current concepts on the role of inflammation in COPD and lung cancer

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Chronic obstructive pulmonary disease (COPD) and lung cancer are leading cause of death, and both are associated with cigarette smoke exposure. It has been shown that 50–70% of patients diagnosed with lung cancer suffer from COPD, and reduced lung function is an important event in lung cancer suggesting an association between COPD and lung cancer. However, a causal relationship between COPD and lung tumorigenesis is not yet fully understood. Recent studies have suggested a central role of chronic inflammation in the pathogenesis of both the diseases. For example, immune dysfunction, abnormal activation of NF-κB, epithelial-to-mesenchymal transition, altered adhesion signaling pathways, and extracellular matrix degradation/altered signaling are the key underlying mechanisms in both COPD and lung cancer. These parameters along with other processes, such as chromatin modifications/epigenetic changes, angiogenesis, and autophagy/apoptosis are altered by cigarette smoke, are crucial in the development of COPD and lung cancer. Understanding the cellular and molecular mechanisms underlying these processes will provide novel avenues for halting the chronic inflammation in COPD and devising therapeutic strategies against lung cancer.

Introduction

Both chronic obstructive pulmonary disease (COPD) and lung cancer are associated with cigarette smoking and/or various environmental pollutants exposure. They represent the fourth-leading and second-leading causes of death in USA and worldwide, respectively. COPD is shown to increase the risk for developing lung cancer [1]. Hence, there are shared mechanisms (e.g. chronic inflammation) in both COPD and lung cancer, or in the progression of COPD which increase the susceptibility for lung tumorigenesis up to 4.5-fold (Figure 1). This review focuses on current knowledge of specific processes/molecules that drive chronic inflammation which are important in the pathogenesis of both COPD and lung cancer, and identify the potential therapeutic targets for these chronic diseases (Figure 2).

Section snippets

Chronic inflammation in COPD and lung cancer

Cigarette smoke contains more than 1014 oxidants/free radicals and 4700 reactive chemical compounds including aldehydes, quinones, semiquinones, nitrosamines, benzo(a)pyrene, and other carcinogens, and it is a risk factor in the development of COPD/emphysema and lung cancer by inducing chronic inflammation. Macrophages, neutrophils, and lymphocytes, the main orchestrators and amplifiers in the progression of COPD, are thought to fight against cancers by eradicating dysplastic and neoplastic

NF-κB pathway in COPD and lung cancer

It is well known that canonical and noncanonical NF-κB pathways play crucial role in the pathogenesis/development of COPD by increasing the release of proinflammatory mediators leading to chronic inflammation in the lung. Indeed, NF-κB-regulated genes including cytokines, adhesion molecules, angiogenic factors, antiapoptotic factors, and matrix metalloproteinases (MMPs) that all have shown to be associated with tumor progression and metastasis. Furthermore, NF-κB in lung epithelium functions as

Adaptive immune response and immunosculpting in COPD and lung cancer

Chronic inflammation of COPD is characterized by the accumulation of neutrophils, macrophages, B cells, CD4+-T, CD8+-T cells, dendritic cells, and eosinophils, particularly in the smaller airways, and the severity of COPD is associated with the infiltration of these inflammatory immune cells. The role of inflammatory cells in COPD has focused on oxidants, proteinases, perforin, and granzymes released from these cells leading to alveolar wall destruction and mucus hypersecretion. Recently, it

Adhesion molecules: integrins and TGF-β pathways in COPD and lung cancer

Integrins are heterodimeric transmembrane receptors, and are involved in a variety of cellular functions as well as in lung inflammation. Integrin αvβ6 is one of the integrins which is located in epithelial cells, and its expression is increased during lung inflammation or injury. Interestingly, integrin αvβ6 plays an important role in maintaining normal lung homeostasis and preventing lung destruction since ablation of integrin αvβ6 leads to airspace enlargement in mice by regulating

Hypoxia/angiogenesis in COPD and lung cancer

Hypoxia is shown to induce pulmonary inflammation by inducing the activation of transcription factor and triggering the expression of proinflammatory genes. In COPD, progressive airflow limitation and destruction of the alveolar capillary may lead to decreased oxygen transport and alveolar hypoxia. In this context, hypoxia-inducible factor (HIF) is activated leading to the enhancement of VEGF transcription and increased angiogenesis. Interestingly, the levels of VEGF and its receptors are

MMPs in COPD and lung cancer

Emphysema is a consequence of an imbalance between antiproteinases and proteinases (balance shifted toward proteinases) including elastase and MMPs from activated inflammatory cells and epithelial cells in lungs. Lungs structural cell death occurs when they lose the attachment because of ECM degradation by MMPs as well as by defective tissue repair. Furthermore, ECM fragments have chemotactic activity to attract inflammatory cells into the lung which aggravates the progression of emphysema in

Cell cycle regulator in COPD and lung cancer

Cigarette smoke is a potent genotoxic stimulus of DNA damage through oxidant stress/carcinogens, thereby arrests cell cycle. It has been shown that the expression of p21CIP1/WAF1/SDI1 (p21), a cyclin-dependent kinase (CDK) inhibitor, is increased in alveolar epithelial cells exposed to cigarette smoke extract, and in alveolar macrophages and biopsies isolated from smokers [28, 29]. Furthermore, the antiapoptotic protein Bcl-XL is increased in alveolar macrophages from smokers suggesting that

Autophagy/apoptosis in COPD and lung cancer

Autophagy is a dynamic process responsible for the turnover of cellular organelles and proteins, which are essential for maintaining cell homeostasis and conferring adaption to adverse environmental stimuli. However, excessive autophagy will lead to cell death. Recently, it has been shown that autophagy regulated the inflammatory immune response via controlling inflammasome activation [35]. Interestingly, increased autophagy and apoptosis of epithelial/endothelial cells are shown to occur in

Chromatin remodeling/epigenetics in COPD and lung cancer

Chromatin remodeling includes post-translational modifications of core histone proteins and DNA methylation which is shown to regulate proinflammatory gene expression during the development of COPD and lung carcinogenesis. Increased histone acetylation is observed on the promoters of proinflammatory genes in airway epithelial cells and alveolar macrophages in patients with COPD, and the degree of acetylation is positively correlated with disease severity [42]. The mechanism that underlies

SIRT1 in COPD and lung cancer

SIRT1, a class III HDAC, is shown to regulate inflammation, senescence, autophagy/apoptosis, and aging by deacetylating histones/nonhistone proteins including transcription factors, coactivators, and other signaling molecules, such as NF-κB, FOXO, HIF-2α, and p53. Anti-inflammatory property of SIRT1 is associated with decreased NF-κB transcriptional activity by deacetylating RelA/p65 at lys310 residue [48]. Given that a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke

Conclusions and future directions

Both COPD and lung cancer are tobacco smoking-associated chronic diseases that cluster in families and aggravate with age, and 50–70% of patients diagnosed with lung cancer have declined spirometric evidence of COPD. Furthermore, reduced lung function (FEV1) is the important event for lung cancer indicating an association between COPD and lung cancer. Nevertheless, a causal relationship between COPD and lung tumorigenesis is not yet known. It is generally accepted that chronic inflammation

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This study was supported by the NIH R01-HL085613 and NIEHS Environmental Health Sciences Center grant ES01247. We apologize for not citing many original articles due to lack of space.

References (50)

  • J.C. Hogg et al.

    The nature of small-airway obstruction in chronic obstructive pulmonary disease

    N Engl J Med

    (2004)
  • J.C. Hogg et al.

    The pathology of chronic obstructive pulmonary disease

    Annu Rev Pathol

    (2009)
  • N. Voelkel et al.

    Emphysema: an autoimmune vascular disease?

    Proc Am Thorac Soc

    (2005)
  • S.H. Lee et al.

    Antielastin autoimmunity in tobacco smoking-induced emphysema

    Nat Med

    (2007)
  • S. Goswami et al.

    Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop

    Cancer Res

    (2005)
  • K. Liu et al.

    CTL adoptive immunotherapy concurrently mediates tumor regression and tumor escape

    J Immunol

    (2006)
  • D.G. Morris et al.

    Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes MMP12-dependent emphysema

    Nature

    (2003)
  • H. Takizawa et al.

    Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD)

    Am J Respir Crit Care Med

    (2001)
  • C. Pilette et al.

    Increased galectin-3 expression and intra-epithelial neutrophils in small airways in severe COPD

    Eur Respir J

    (2007)
  • S. Gebel et al.

    The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression

    Toxicol Sci

    (2006)
  • H.O. Abdel-Aziz et al.

    Targeted disruption of the galectin-3 gene results in decreased susceptibility to NNK-induced lung tumorigenesis: an oligonucleotide microarray study

    J Cancer Res Clin Oncol

    (2008)
  • S.E. Michaud et al.

    Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: impairment of the HIF-1alpha/VEGF pathway

    FASEB J

    (2003)
  • I. Edirisinghe et al.

    VEGFR-2 inhibition augments cigarette smoke-induced oxidative stress and inflammatory responses leading to endothelial dysfunction

    FASEB J

    (2008)
  • Y. Kasahara et al.

    Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

    J Clin Invest

    (2000)
  • N.M. Siafakas et al.

    Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease

    Int J Chron Obstruct Pulmon Dis

    (2007)
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