VEGF obstructs the lungs
[refers to the same article as the earlier post]
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Nature Medicine 10, 1041 - 1042 (2004)
doi:10.1038/nm1004-1041
VEGF obstructs the lungs
Marc E Rothenberg
Marc E. Rothenberg is at Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229 USA. rothenberg@cchmc.org
Vascular endothelial growth factor (VEGF), known as a mediator of blood vessel formation and permeability, now gains an essential position in allergic lung responses (pages 1095–1103).
As we enter the new millennium, one of the paradoxes of modern medicine is the rapidly growing incidence of immune-based diseases (1). In fact, immune hypersensitivity responses are central to many common diseases of the twenty-first century, including atherosclerosis, diabetes, obesity and arthritis (2). Included in this epidemic are allergic disorders—asthma, eczema, allergic rhinoconjunctivitis and food allergies—which have skyrocketed over the past half-century, increasing threefold in prevalence. In the United States, nearly 30% of the population now suffers from allergies, including asthma, which ramps up annual health care costs of 18 billion dollars (3).
Mechanistic studies have identified an essential role for type 2 T helper cells (TH2 cells) in the generation and orchestration of allergic responses; these cells release specific cytokines that regulate allergy-associated pathology (3). In this issue, Lee et al. (4) further our understanding of allergic responses by reporting that the cytokine vascular endothelial growth factor (VEGF), a critical regulator of new blood vessel formation, cooperates with TH2 cells in the development of allergic lung responses, at least in an experimental model of asthma in mice.
Emerging evidence indicates that the rising incidence of allergic disorders is related to changes in western lifestyle. For instance, people spend more time indoors exposed to common antigens, such as those from fungi and dust mites, and they use more antibiotics and vaccines, which alter infection patterns and endogenous flora. This less challenging pathogen burden allows the immune system to become delinquent, available to react to innocuous antigens (allergens). Whereas the normal response to airborne molecules is tolerance, allergic individuals are predisposed to aberrant T-cell regulation.
TH2 cells induce many of the features of asthma through the secretion of cytokines (such as interleukin (IL)-4, IL-5, IL-9 and IL-13) that activate inflammatory and respiratory cell effector pathways. These features generally include eosinophil-rich inflammation, IgE production and chronic lung remodeling (mucus production, smooth muscle hyperplasia and fibrosis)5. Additionally, recent studies have drawn attention to antigen-presenting dendritic cells that preferentially promote the generation of TH2 cells.
In the clinic, glucocorticoids, cysteinyl-leukotriene inhibitors and anti-IgE therapeutics are only partly effective, reflecting the interplay of multiple cells, cytokines and mediators in disease pathogenesis. Furthermore, these therapeutic approaches may have only limited benefit in improving chronic lung remodeling (6). New approaches are clearly needed.
VEGF is upregulated in a variety of inflammatory disorders including arthritis, psoriasis and asthma. In individuals with asthma, overexpression of VEGF on inflammatory cells is inversely correlated with airway function (7). It has been proposed that VEGF overexpression increases vascular permeability (edema) in asthmatics (8). Furthermore, numerous reports have shown increases in lung vasculature in asthmatics and strong correlations between the degree of vascular abnormalities and asthma severity (9). Despite these provocative findings, the specific contribution of VEGF in asthmatic responses had not been directly addressed.
Lee et al. set out to do just this. The authors first overexpressed an inducible form of VEGF in the mouse lung; as might be expected, this treatment promoted marked neovascularization and edema in the lung. But VEGF expression had far more profound consequences, dramatically affecting multiple markers of lung inflammation, increasing the number of infiltrating leukocytes, promoting lung remodeling (mainly increasing collagen deposition, myocyte hyperplasia and formation of mucus-secreting goblet cells), and increasing the responsiveness of the lung to stimuli (airway hyper-responsiveness).
The investigators went on to show that the VEGF transgenic mice overproduced IL-13, known to direct production of mucus, adhesion molecules and chemokines in airway cells. Moreover, the ability of VEGF to induce mucus was abrogated in IL-13-deficient mice. These results dovetail with prior observations that IL-13 induces VEGF overexpression (10), suggesting that VEGF and IL-13 participate in a feedback loop.
Investigating the broader effect of VEGF, the investigators showed that transgenic mice have elevated numbers of activated dendritic cells and that they develop an exaggerated allergic immune response when exposed to a respiratory antigen. Finally, the authors implicated VEGF in the development of antigen-induced experimental asthma. They first localized VEGF production to airway epithelium and TH2 cells. They then showed that abrogation of VEGF function partly protected the mice from certain features of experimental asthma, including inflammatory cell numbers, airway hyper-responsiveness and IL-13 production.
These results draw attention to the role of VEGF in promoting tissue remodeling and antigen sensitization in the lung (Fig. 1 and 2). Perhaps induction of VEGF in early life may promote subsequent development of antigen sensitization and TH2-associated diseases. Recently, Whitsett and colleagues also overexpressed VEGF in the lung with the same transgenic system as Lee's group (11). The investigators did not focus on immunity, and, unlike Lee et al., who induced VEGF after a month, they induced the gene right after birth. Alveolar leakage and alterations in pulmonary vasculature development were observed. But the mice also experienced pulmonary hemorrhage, hemosiderosis, emphysema (air space enlargement) and death (11). Thus, VEGF overexpression in the early postnatal lung can promote lung disease well beyond TH2-associated disease (11). Indeed, VEGF has been shown to increase in a variety of TH1-associated states; even Lee et al. show that TH1 cells express VEGF, albeit at lower levels than TH2 cells.
These results are notable on several grounds, and have immediate clinical implications. Anti-VEGF therapies have recently been approved for the treatment of patients with renal cell carcinoma, and it will be important to examine respiratory parameters in patients currently being treated for cancer. The results of the study by Lee et al. (4) should also propel the design of studies specifically aimed at assessing the role of VEGF therapeutics in allergic inflammation. In the past, there was reluctance to use cancer therapeutics for the treatment of allergic disease, mainly because of toxicity. But there is a high degree of in situ cell proliferation in the asthmatic lung. Indeed, a number of rapidly emerging, relatively safe cancer therapeutics may soon benefit allergy sufferers.
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4. Lee, C.G. et al. Nat. Med. 10, 1095–1103 (2004).
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11. Le Cras, T.D. et al. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L134–L142 (2004).
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