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Hepatocyte Growth Factor Deficiency in COPDHepatocyte Growth Factor in COPD: A Mechanism of Emphysema and Small Airway Fibrosis? FREE TO VIEW

Peter J. Barnes, DM, DSc, Master FCCP
Author and Funding Information

From the Airway Disease Section, National Heart & Lung Institute, Imperial College London.

CORRESPONDENCE TO: Peter J. Barnes, DM, DSc, Master FCCP, Airway Disease Section, National Heart & Lung Institute, Dovehouse St, London, SW3 6LY, England; e-mail: p.j.barnes@imperial.ac.uk


FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(5):1135-1136. doi:10.1378/chest.14-1194
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Hepatocyte growth factor (HGF) (previously known as scatter factor) is a multifunctional cytokine that is secreted by mesenchymal cells, such as fibroblasts, and has effects on epithelial cell growth, morphogenesis, motility, and survival that are mediated by the proto-oncogenic receptor c-Met.1 It plays a key role in the development of organs such as the lung, where it promotes branching of airways and alveolar formation and has been implicated in lung repair.2 Stem cells expressing HGF have been identified in human lung and, by extrapolation from animal studies, are antifibrotic.3 Studies have shown that in mice deficient in c-Met there is a loss of alveolar wall integrity due to loss of alveolar cells, attenuation of the pulmonary vasculature, and an increase in oxidative stress, closely analogous to emphysema. Furthermore, treatment of primary alveolar cells with HGF promotes cell survival and enhanced production of antioxidants.4 Fibroblasts cultured from emphysematous lung produce less HGF than normal and it has been implicated in impaired alveolar repair in emphysema.5 With this background, it is surprising that so little attention has been paid to the role of HGF in COPD. However, in this issue of CHEST (see page 1159), Kanazawa et al,6 in a clinical study from Japan, show convincing evidence for reduced secretion of HGF in peripheral lung of patients with COPD compared with age-matched normal smokers and healthy control subjects and that this is correlated with disease severity and reduced gas transfer. This is consistent with a reduction in HGF having a role in emphysema, and, indeed, there is also a correlation between reduced HGF concentrations and low attenuation areas (emphysema) on the CT scan.

In the same study, the investigators also found a reduction of vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis that prevents endothelial cell apoptosis. This confirms previous reports of reduced VEGF expression and its receptor in emphysema.7,8 Indeed, there is a close correlation between the concentrations of HGF and VEGF in extracellular lining fluid of peripheral airway in patients with COPD and both correlate with disease severity (FEV1 % predicted) and with the extent of emphysema measured by CT scanning. While the effects of HGF are predominantly in epithelial cells, it also has effects on endothelial cell function and may be synergistic with VEGF which specifically targets endothelial cells. The mechanisms for the reduction in both HGF and VEGF are uncertain. Oxidative stress is markedly increased in the peripheral lung of patients with COPD.9 Oxidative stress may suppress HGF secretion from fibroblasts, resulting in epithelial cell dysfunction and apoptosis, which in turn may reduce VEGF secretion, thus, affecting endothelial cell integrity. HGF is generated from an inactive precursor (pro-HGF) that may be activated by plasminogen activator. Plasminogen activator inhibitor-1 is increased in COPD, probably in response to oxidative stress through activation of the transcription factor nuclear factor-κB, providing another mechanism that may inhibit HGF activity in COPD.10

A very interesting finding is the differences found in extracellular lining fluid from peripheral compared with central airways. Most measurements of airway secretions have used induced sputum of BAL to obtain luminal samples, but Kodama et al11 used a bronchoscopic microcatheter that directly samples fluid from peripheral airways. COPD mainly affects peripheral airways and lung parenchyma, and it is likely that small airway disease is the initial lesion in COPD.12 HGF was found in much higher concentrations in peripheral airways of healthy smokers and nonsmokers than in central airways, but in patients with COPD peripheral airway concentrations of HGF were reduced to a level similar to that in central airways.6 With VEGF, however, the concentrations were greater in peripheral than central airways of nonsmokers whereas concentrations in peripheral airways of normal smokers were reduced and even more reduced in patients with COPD. In normal smokers, there was even an elevation of HGF in peripheral airways, and it is possible that this may have compensated for the reduced VEGF concentrations to protect against endothelial apoptosis. The low concentrations of HGF in peripheral airways of patients with COPD may facilitate the development of peribronchiolar fibrosis as HGF is protective against the development of fibrosis though inhibiting the effects of the fibrogenic mediator transforming growth factor-β, whereas the high concentrations in normal smokers may prevent the development of fibrosis.

What are the therapeutic implications of this study? HGF has been considered as a potential therapy for fibrotic diseases administered as a protein or via stem cells as gene therapy. A recent study showed that adenovirus-HGF modified mesenchymal stem cells protected against radiation-induced lung fibrosis in mice.13 Other strategies might include therapies that enhance endogenous HGF secretion through a better understanding of the pathways leading to its reduction in patients with COPD.14 However, HGF and c-Met have been implicated in non-small-cell lung cancer, which is a high risk in patients with COPD.15 Further research on the role of HGF in COPD is likely to be profitable and may lead to a better understanding of the pathogenesis of emphysema and small airway fibrosis as well as novel therapeutic approaches.

References

Naldini L, Weidner KM, Vigna E, et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991;10(10):2867-2878. [PubMed]
 
Ohmichi H, Koshimizu U, Matsumoto K, Nakamura T. Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development. Development. 1998;125(7):1315-1324. [PubMed]
 
Gazdhar A, Susuri N, Hostettler K, et al. HGF expressing stem cells in usual interstitial pneumonia originate from the bone marrow and are antifibrotic. PLoS ONE. 2013;8(6):e65453. [CrossRef] [PubMed]
 
Calvi C, Podowski M, Lopez-Mercado A, et al. Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. PLoS Genet. 2013;9(2):e1003228. [CrossRef] [PubMed]
 
Plantier L, Marchand-Adam S, Marchal-Sommé J, et al. Defect of hepatocyte growth factor production by fibroblasts in human pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol. 2005;288(4):L641-L647. [CrossRef] [PubMed]
 
Kanazawa H, Tochino Y, Asai K, Hirata K. Simultaneous assessment of hepatocyte growth factor and vascular endothelial growth factor in epithelial lining fluid from patients with COPD. Chest. 2014;146(5):1159-1165.
 
Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med. 2001;163(3 pt 1):737-744. [CrossRef] [PubMed]
 
Kanazawa H, Asai K, Hirata K, Yoshikawa J. Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Am J Med. 2003;114(5):354-358. [CrossRef] [PubMed]
 
Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144(1):266-273. [CrossRef] [PubMed]
 
To M, Takagi D, Akashi K, et al. Sputum plasminogen activator inhibitor-1 elevation by oxidative stress-dependent nuclear factor-κB activation in COPD. Chest. 2013;144(2):515-521. [CrossRef] [PubMed]
 
Kodama T, Kanazawa H, Tochino Y, Kyoh S, Asai K, Hirata K. A technological advance comparing epithelial lining fluid from different regions of the lung in smokers. Respir Med. 2009;103(1):35-40. [CrossRef] [PubMed]
 
McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567-1575. [CrossRef] [PubMed]
 
Wang H, Yang YF, Zhao L, et al. Hepatocyte growth factor gene-modified mesenchymal stem cells reduce radiation-induced lung injury. Hum Gene Ther. 2013;24(3):343-353. [CrossRef] [PubMed]
 
Chakraborty S, Chopra P, Hak A, Dastidar SG, Ray A. Hepatocyte growth factor is an attractive target for the treatment of pulmonary fibrosis. Expert Opin Investig Drugs. 2013;22(4):499-515. [CrossRef] [PubMed]
 
Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1089-1096. [CrossRef] [PubMed]
 

Figures

Tables

References

Naldini L, Weidner KM, Vigna E, et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991;10(10):2867-2878. [PubMed]
 
Ohmichi H, Koshimizu U, Matsumoto K, Nakamura T. Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development. Development. 1998;125(7):1315-1324. [PubMed]
 
Gazdhar A, Susuri N, Hostettler K, et al. HGF expressing stem cells in usual interstitial pneumonia originate from the bone marrow and are antifibrotic. PLoS ONE. 2013;8(6):e65453. [CrossRef] [PubMed]
 
Calvi C, Podowski M, Lopez-Mercado A, et al. Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. PLoS Genet. 2013;9(2):e1003228. [CrossRef] [PubMed]
 
Plantier L, Marchand-Adam S, Marchal-Sommé J, et al. Defect of hepatocyte growth factor production by fibroblasts in human pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol. 2005;288(4):L641-L647. [CrossRef] [PubMed]
 
Kanazawa H, Tochino Y, Asai K, Hirata K. Simultaneous assessment of hepatocyte growth factor and vascular endothelial growth factor in epithelial lining fluid from patients with COPD. Chest. 2014;146(5):1159-1165.
 
Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med. 2001;163(3 pt 1):737-744. [CrossRef] [PubMed]
 
Kanazawa H, Asai K, Hirata K, Yoshikawa J. Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Am J Med. 2003;114(5):354-358. [CrossRef] [PubMed]
 
Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144(1):266-273. [CrossRef] [PubMed]
 
To M, Takagi D, Akashi K, et al. Sputum plasminogen activator inhibitor-1 elevation by oxidative stress-dependent nuclear factor-κB activation in COPD. Chest. 2013;144(2):515-521. [CrossRef] [PubMed]
 
Kodama T, Kanazawa H, Tochino Y, Kyoh S, Asai K, Hirata K. A technological advance comparing epithelial lining fluid from different regions of the lung in smokers. Respir Med. 2009;103(1):35-40. [CrossRef] [PubMed]
 
McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567-1575. [CrossRef] [PubMed]
 
Wang H, Yang YF, Zhao L, et al. Hepatocyte growth factor gene-modified mesenchymal stem cells reduce radiation-induced lung injury. Hum Gene Ther. 2013;24(3):343-353. [CrossRef] [PubMed]
 
Chakraborty S, Chopra P, Hak A, Dastidar SG, Ray A. Hepatocyte growth factor is an attractive target for the treatment of pulmonary fibrosis. Expert Opin Investig Drugs. 2013;22(4):499-515. [CrossRef] [PubMed]
 
Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1089-1096. [CrossRef] [PubMed]
 
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