PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Immunol Cell Biol. Author manuscript; available in PMC 2010 April 7.
Published in final edited form as:
Immunol Cell Biol. 2009 Nov–Dec; 87(8): 601–605.
Published online 2009 June 23. doi:  10.1038/icb.2009.45
PMCID: PMC2850593
NIHMSID: NIHMS180055

Why is effective treatment of asthma so difficult? An integrated systems biology hypothesis of asthma

Abstract

A hypothesis is presented that asthma is not only an airway disease, but that the disease involves the entire lung, and that the chronicity of asthma and asthma exacerbations can perhaps be explained if one considers asthma as a systemic disease. Increased lung—not only airway—vascularity may be the result of the action of angiogenesis factors, such as vascular endothelial growth factor (VEGF) and sphingosine-1-phosphate (S1P). A bone-marrow lung axis can be postulated as one element of the systemic nature of the asthma syndrome, in which the inflamed lung emits chemotactic signals, which the bone marrow responds to by releasing cells that contribute to lung angiogenesis. A molecular model of the pathobiology of asthma can be built by connecting hypoxia-inducible transcription factor-1 alpha, VEGF S1P, and bone-marrow precursor cell mobilization and acknowledging that angiogenesis is part of the inflammatory response.

Keywords: angiogenesis, asthma, bone marrow, HIF-1α, systems disease, VEGF

Asthma is a major world-wide health problem; more people are contracting asthma,1 perhaps because of an increasingly toxic environment2 and/or a diminishing exposure of infants to dirt and farm animals.3 Gene hunters have tracked genes that may predispose to atopic reactions and to ‘jittery’ airways—airway hyperreactivity.4 The repertoire of treatments for asthma has recently been expanded from the use of β-adrenergic antagonists and inhaled steroids to include antibodies directed against TNF-α and IgE.5,6 The list of important mediators of airway smooth muscle contraction and inflammation was initially short: histamine, acetylcholine, and slow-reacting substance of anaphylaxis—eventually shown to be leukotrienes, arachidonic acid metabolites produced by eosinophils, and mast cells that were clearly identified in the airways of asthma patients.7

More recently, the term ‘remodeling’ has been added to describe structural changes of the small bronchi in asthma, such as fibrosis, smooth muscle hypertrophy, and epithelial cell hyperplasia,810 which may explain why conventional bronchodilator drugs are not effective or why the disease is often irreversible. Viral11 and mycoplasma infections12,13 are being considered as trigger factors, and obesity has recently captured the attention of asthma researchers.14 There are different presentations of the asthma syndrome, and different ‘phenotypes’ and exacerbations of eosinophilic asthma have recently been shown to be reduced by treatment of these patients with an anti-interleukin 5 monoclonal antibody.15

WHERE THE PROBLEM MAY BE

As asthma presents with airway hyperreactivity and bronchospasm, the tacit assumption has been that asthma is overwhelmingly or entirely an airway disease.16,17 Although clinicians and researchers used to make a distinction between extrinsic and intrinsic forms of asthma, the bronchial tree is the target of the immune response and the combat zone of inflammatory cells and mediators. Some investigators have recently questioned whether a strict compartmental approach to chronic and progressive lung diseases has narrowed our view and denied access to critical cues and information, which can only be obtained if one considers a more holistic viewpoint, that is the entire lung is involved and asthma is in fact a systemic disease.18,19

HYPOTHESIS

The hypothesis entertained here is that asthma is not only an airway disease, but also a vascular disease. A second element of the overall hypothesis is that the chronicity of the asthma syndrome is maintained by bone-marrow-derived precursor cells.

Hyperemic bronchial mucosa in asthma has been recognized for many years.2023 Bronchial biopsy studies have repeatedly documented hypervascularity,23,24 and this phenomenon has been explained as part of the airway inflammation (calor, rubor). Yet, recent data document that one powerful endothelial cell growth factor and important angiogenesis factor—vascular endothelial growth factor (VEGF)—is also overexpressed in the lung parenchyma and the supernormal diffusing capacity (DLCO, total lung diffusing capacity, a standardized measure of the diffusion of carbon monoxide across lung capillary menbranes) measured in some patients with asthma25 is consistent with the concept that the asthmatic lung has more vessels and more capillaries. A hypervascularized lung is likely to produce symptoms of a ‘congested lung’. Anti-inflammatory asthma therapy may work because it affects the vascularity of the bronchi and of the lung parenchyma, and thus reduces swelling (congestion). It is surprising that in the mind of many investigators, hypervascularity is restricted to the airway mucosa.

ASTHMA AND ANGIOGENESIS

The hypoxia-inducible transcription factor-1 alpha (HIF-1α) binds to hypoxia-response elements in the promoters of many genes involved in the adaptation to an environment of insufficient oxygen or hypoxia. Lee et al.26 examined the levels of VEGF and HIF-1α in the bronchial mucosa of patients with asthma by immunohistochemistry and found increased expression of both proteins. Mast cells, which are known to be a source of increased airway production of VEGF,27 can mediate an increase in vascular permeability through HIF-1α/VEGF,28 but mechanical strain of airway smooth muscle can also increase expression of HIF-1α and VEGF.29 The relationship between VEGF-dependent airway angiogenesis and its regression and airway remodeling in the mouse has been investigated by McDonald and co-workers.30,31 Airway smooth muscle cells from asthmatic patients promote in vitro angiogenesis and BALF from asthmatic patients promotes angiogenesis.32 VEGF serum levels were found to be elevated in patients with Churg–Strauss syndrome33 and in patients with toluene diisocyanate-induced asthma.34 Elias and his group have shown that VEGF induces an asthma-like phenotype and that nitric oxide (NO) mediates VEGF-induced pulmonary angiogenesis and airway hyperreactivity.35,36 Asthma is also a syndrome that is associated with enhanced lymphoangiogenesis mediated by VEGF-C and VEGF-D through the VEGFR3.37

HYPOXIA-INDUCIBLE TRANSCRIPTION FACTOR-1 ALPHA

Lee et al.26 reported increased expression of HIF-1α protein in the airway mucosa of patients with asthma; this is to our knowledge the only published report to date, which has attempted to link HIF-1α and clinical asthma. Of interest in regards to a ‘viral triggers of asthma’ hypothesis3840 are the observations that human rhinovirus,41 RSV,42,43 and EBV44 all induce stabilization of HIF-1α. House dust mite exposure causes airway remodeling in mice45 and non-human primates is associated with increased airway and lung tissue VEGF expression;46 however, HIF-1α expression was not measured in these experiments.

Although HIF-1α has been examined in the context of cancer/malignancy and hypoxia, there is a growing appreciation of its central role in inflammation, and that NF-κB, a transcription factor that promotes cytokine expression, links innate immunity to the hypoxic response through transcriptional control of HIF-1α.47 In tissue foci of inflammation, to maintain homeostasis, phagocytic cells (as part of the inflammation paradigm) generate ATP through glycolysis, and virtually every enzyme of the glycolytic pathway is transcriptionally controlled by HIF-1α.48 HIF-1α may contribute to increased airway smooth muscle contractility.49 Voelkel and co-workers have found that inhibition of VEGFRs inhibits phagocytic uptake of apoptosed cells. In this case, the inhibited VEGF receptors are on macrophages, illustrating one of the roles of VEGF signaling in the context of resolution of inflammation. Indeed, hypoxia causes an increase in phagocytosis by macrophages in an HIF-1α-dependent manner,50 and induces endothelial cell proliferation through Akt.51 HIF-1α myeloid-null mice have greatly diminished joint swelling and cartilage destruction in an arthritis model.52

Loss of HIF-1α expression in fibroblasts accelerates the onset of cellular senescence.53 Bone-marrow-derived mesenchymal cells depend on HIF-1α expression to express VEGFR1 and migrate in response to VEGF.54 In the absense of HIF-1α, fewer endothelial cell precursors are recruited to tumors,55 whereas HIF-1α overexpression mobilizes circulating angiogenic cells.56 Copper is involved in activation of HIF-1α by regulating its binding to the hypoxia-response element of target genes.57 This fact is of interest in the context of particulate air pollution and sensitivity of ashtmatic individuals to inhaled particles. Kennedy et al.58 detected Cu++ in air pollution particulates and showed Cu++-dependent IL-6 and IL-8 stimulation in bronchial epithelial cells. Copper can stimulate cell proliferation through HIF-1α and facilitate epithelial-to-mesenchymal transition and fibrosis.59,60 Thus, highly active HIF-1α could contribute both to angiogenesis (hypervascularity) and fibrotic airway remodeling in asthma. One study indeed reported elevated serum copper levels in patients with asthma.61

· NO

Numerous reports have described increased exhaled ·NO in patients with asthma,62 although standardization of the methodology and confounding factors have not led to the establishment of exhaled ·NO as a reliable biomarker of asthma disease activity.63 There are also complicated interactions between ·NO and VEGF. For example, incubation of endothelial cells with VEGF causes eNOS activation and ·NO production,64 and VEGF upregulates eNOS in lung epithelium.65 Bhandari et al.35 pointed out that ·NO plays a critical role in VEGF-induced asthma-like lung responses. On the other hand, ·NO modulates the HIF-1α-dependent induction of prolyl hydroxylase 2, the enzyme responsible for HIF-1α protein stabilization.64

ASTHMA AND BONE MARROW

A lung/bone-marrow functional interaction is now apparent to a number of lung researchers. Mobilization of hematopoetic progenitor cells from the bone marrow is a feature of the inflammatory asthmatic responses.6668 We postulate that both the chronicity of the asthma syndrome and also part of the angiogenesis of the asthma lung can be explained by actions of cells developed from bone-marrow-derived progenitors. A few investigations have examined the response of the bone marrow and precursor cell release into the circulation in patients with asthma after antigen inhalation challenge,6668 and Asosingh et al.69 reported increased endothelial cell precursor cells in the circulation of asthma patients. Anti-chemokine receptor 3 antibodies inhibited migration of bone-marrow-derived CD34+ progenitor cells,70 and IL-5 inhalation was shown to increase eosinophils in the bone marrow and in the bronchi of asthma patients.71 Nakae et al.72 proposed that bone-marrow-derived mast cells are not required for the induction of ovalbumin (OVA)-specific memory T lymphocytes, but are required for increased lymphocyte recruitment in the lung during the challenge phase. Reuter et al.73 used a more acute OVA sensitization (without adjuvant) and challenge, confirming that bone-marrow-derived mast cells from wild-type (WT) mice, but not from TNF−/− mice, reconstituted the lung inflammation in sensitized and challenged mast cell deficient mice. Although these experiments document the mast cell dependency of the OVA-induced asthma model, they do not rigorously test the bone-marrow dependency. We now suggest an experimental approach that will focus on the bone-marrow dependency of lung inflammation, and will answer the question of whether the OVA-induced response in the lung is reduced in HIF-1α−/+ mice, but can be reconstituted by transplant of WT bone marrow. Finally, Gomperts and Strieter74 make a case for fibrocytes (which are also antigen presenting cells and have angiogenic properties) as bone-marrow-derived cells. Nihlberg et al.75 identified fibrocytes in the airways of patients with asthma. Taken together, in our opinion it is plausible that the bone marrow can deliver cells that directly or indirectly drive angiogenesis in the ‘asthma lung’. CD34−/− mice show a mitigated asthma lung phenotype, which is due to a bone-marrow cell mobilization defect.76 Interestingly, the role of VEGF produced in the inflamed lung and spilling over into the systemic circulation has not been considered as playing a role in the release of bone-marrow progenitors in asthma. However, it has been reported that allergic lung inflammation promotes the recruitment of circulating tumor cells to the lung.77 It will not be difficult for readers to accept such a concept of an important bone-marrow contribution to the pathobiology of asthma, which is neither taught in medical school nor is the basis of particular treatment strategies.

ASTHMA AND SPHINGOSINE-1-PHOSPHATE

Recent data place sphingosine-1-phosphate (S1P) into the asthma paradigm of inflammation and immune response.7880 S1P levels are mainly regulated by a particular cell’s enzymatic activity—sphingosine kinases and sphingosine lysase and phosphatases.80 Many cells have the capacity to produce and respond to S1P, yet S1P levels are low in tissue and much higher in blood and lymph. Most of the actions of S1P are mediated by binding to five specific G protein-coupled receptors, designated S1P1–5. S1P1, S1P2, and S1P3 receptors play a role in vascular tone regulation, control of endothelial cell barrier function,81,82 and endothelial cell proliferation.83,84 Tanimoto et al.85 showed that S1P activates eNOS through VEGFR2 (KDR). Thus, S1P has not only been shown to cause airway hyperreactivity86 and OVA-induced airway inflammation,87,88 but also plays a role in lung capillary tube formation89 and closely interacts with VEGF and eNOS. This suggests that S1P may be important for asthma angiogenesis,90,91 in particular as sphingosine kinase-1 is an HIF-1α regulated gene and S1P stimulates endothelial cell migration through S1P1.9294 Moreover, Venkataraman et al.95 provided evidence that the endothelium is a major contributor to the plasma S1P levels. Earlier studies suggest that increases in levels of ceramide, the precursor of S1P, cause pulmonary cell apoptosis and emphysema-like disease in mice.96 Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress, and emphysema caused by blockade of the VEGF receptors. Interestingly, concomitant addition of S1P prevented lung apoptosis, implying that a balance between ceramide and S1P is important for maintenance of alveolar septal integrity. Taken together, we postulate a lung structure homeostatic balance between ceramide, which is increased in pulmonary emphysema, and S1P, which is increased in asthma. With some degree of over-simplification ceramide is proapoptotic and anti-angiogenic, whereas S1P is anti-apoptotic and pro-angiogenic (Figure 1).

Figure 1
This schematic depicts known interactions between VEGF and S1P. These interactions are both on the ligand as well as the receptor level. The transcription factor HIF-1α is upstream of both VEGF and SphK1.

HOW THE HYPOTHESIS COULD BE TESTED

A few scenarios are sketched here to illustrate how one might experimentally approach our hypothesis. The OVA mouse model of airway hyperreactivity and lung inflammation could be the model of choice simply because of the availability of KO mice, which can be used to take the system apart and to connect the dots. For example, the HIF-1α+/− mouse should not develop airway hyperreactivity and the characteristic lung inflammation if HIF-1α-dependent VEGF upregulation is of importance. VEGF receptor blockade should be similarly effective and S1P–S1P receptor interactions can be specifically probed. To investigate the mobilization of bone-marrow-derived precursor cells, mice with labeled bone-marrow cells can be used and bone marrow from OVA challenged mice—both WT and KO mice—can be transplanted into OVA naïve animals to explore whether any part of the asthma syndrome can be transferred. There are a number of additional experimental strategies to affect HIF-1α protein stability92 and pharmacological inhibitors of S1P receptors are also available.93

SUMMARY AND SIGNIFICANCE

In spite of numerous attempts to control asthma by treatment with bronchodilators, steroids, antigen-directed desenstitization, and IgE-directed therapy, use of leukotriene receptor blockers and mast cell release inhibitors, a true control of the asthma syndrome with its multiple manifestations (exercise-induced, nocturnal, steroid-resistant, etc.), has so far eluded us. Perhaps the reason is that neither eosinophils nor mast cells nor leukotrienes are central enough in a disease that is perhaps much more an integrated system problem than only a bronchial problem. Work in recent years has confirmed that the bone-marrow participates,6669 whereas the evidence supporting that asthma is a systemic disease is not yet particularly strong.18,19,94 We can say that there is a bone-marrow lung axis. We ask whether there are factors that tie together the actions of all or most of the asthma pathobiology players? If we connect all (or most) of the dots, do we find a superstructure or organizing principle, which allows us to understand how inflammation, airway reactivity, immune response, angiogenesis and airway remodeling97 hang together? We are not proposing a theory of ‘everything’, but suggest that HIF-1α-dependent cellular deregulation may be a large part of this superstructure or organizing principle, which transcends the activation of one particular cell type.

Our hypothesis and the proposed research are based not on a reductionist’s approach, they are rather based on a synthesis of facts and findings. As we connect the dots, we see two principles emerging: (1) angiogenesis is part of the pathogenesis of asthma and (2) the bone marrow delivers cells, which maintain the chronicity of asthma and the angiogenic state of the asthma lung. Successful modulation of HIF-1α, a master controller of events,98101 may lead us to a very different new treatment strategy of asthma.102

The acceptance of a significant contribution of the angiogenic tissue response to the pathobiology of asthma will require (a) further documentation and mechanistic explanation of angiogenesis in the asthmatic lung, (b) experimental evidence that anti-angiogenesis is overall beneficial, that is improves asthma, and103,104 (c) a detailed investigation of the interactions between the lung and the bone marrow that drives and maintains lung angiogenesis in asthma.

Bronchospasm and hyperreactive airways naturally focus the attentions of the asthma researchers on the airways to the exclusion of the lung at large and the involvement of other parts of the body. When an asthma patient states that he or she feels ‘congested’, then this is a symptom identical to that described by the patient with ‘congestive’ heart failure. Patients with congestive heart failure can wheeze and the clinicians of past decades had coined the term ‘cardiac asthma’. It is, therefore, peculiar that the non-cardiac asthma symptom of congestion is not understood as caused by the lung being overfilled with blood, whereas the cardiologist visualizes how the blood backs up and congests the lung in mitral valve stenosis. One step in the direction toward a better understanding of asthma is to consider that asthma is a disease of the entire lung, and that it is not restricted to the airways. A too narrow definition or classification of the asthma syndrome may hinder the discovery of causative factors and delay the acceptance of such factors. Likewise, to assume that allergic or non-allergic asthma begins and ends in the airways may blind us to the existence of systemic factors, which may drive the chronicity and exacerbations of asthma.

References

1. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355:2226–2235. [PubMed]
2. Toren K, Blanc PD. Asthma caused by occupational exposures is common—a systematic analysis of estimates of the population-attributable fraction. BMC Pulm Med. 2009;9:7. [PMC free article] [PubMed]
3. Leynaert B, Neukirch C, Jarvis D, Chinn S, Burney P, Neukirch F. Does living on a farm during childhood protect against asthma, allergic rhinitis, and atopy in adulthood? Am J Respir Crit Care Med. 2001;164(10 Pt 1):1829–1834. [PubMed]
4. Willis-Owen SA, Cookson WO, Moffatt MF. Genome-wide association studies in the genetics of asthma. Curr Allergy Asthma Rep. 2009;9:3–9. [PubMed]
5. Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlen SE, et al. A randomized, double-blind, placebo-controlled study of TNF-{alpha} blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179:549–558. [PubMed]
6. D’Amato G. Role of anti-IgE monoclonal antibody (omalizumab) in the treatment of bronchial asthma and allergic respiratory diseases. Eur J Pharmacol. 2006;533:302–307. [PubMed]
7. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med. 2002;346:1699–1705. [PubMed]
8. Bai TR, Knight DA. Structural changes in the airways in asthma: observations and consequences. Clin Sci (Lond) 2005;108:463–477. [PubMed]
9. Bergeron C, Et Boulet L. Structural changes in airway diseases: characteritics, mechanisms, consequences, and pharmacologic modulation. Chest. 2006;129:1068–1087. [PubMed]
10. Chetta A, Zanini A, Foresi A, D’Ippolito R, Tipa A, Castagnaro A, et al. Vascular endothelial growth factor up-regulation and bronchial wall remodelling in asthma. Clin Exp Allergy. 2005;35:1437–1442. [PubMed]
11. Jartti T, Lehtinen P, Vuorinen T, Ruuskanen O. Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics. Pediatr Infect Dis J. 2009;4:311–317. [PubMed]
12. Ou CY, Tseng YF, Chiou YH, Nong BR, Huang YF, Hsieh KS. The role of mycoplasma pneumoniae in acute exacerbation of asthma in children. Acta Paediatr Taiwan. 2008;49:14–18. [PubMed]
13. Kjaer BB, Jensen JS, Nielsen KG, Fomsgaard A, Bottiger B, Dohn B, et al. Lung function and bronchial responsiveness after mycoplasma pneumoniae infection in early childhood. Pediatr Pulmonol. 2008;43:567–575. [PubMed]
14. Sood A, Cui X, Qualls C, Beckett WS, Gross MD, Steffes MW, et al. Association between asthma and serum adiponectin concentration in women. Thorax. 2008;63:877–882. [PMC free article] [PubMed]
15. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–984. [PMC free article] [PubMed]
16. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8:183–192. [PubMed]
17. Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118:3546–3556. [PMC free article] [PubMed]
18. Bjermer L. Time for a paradigm shift in asthma treatment: from relieving bronchospasm to controlling systemic inflammation. J Allergy Clin Immunol. 2007;120:1269–1275. [PubMed]
19. Pucci S, Incorvaia C. Allergy as an organ and a systemic disease. Clin Exp Immunol. 2008;153(Suppl 1):1–2. [PubMed]
20. Hogg JC. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax. 1999;54:283. [PMC free article] [PubMed]
21. Orsida BE, Li X, Hickey B, Wilson JW, Walters EH. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax. 1999;54:289–295. [PMC free article] [PubMed]
22. Li X, Wilson JW. Increased vascularity of the bronchial mucosa in mild asthma. Am J Respir Crit Care Med. 1997;156:229–233. [PubMed]
23. Wilson JW, Hii S. The importance of the airway microvasculature in asthma. Curr Opin Allergy Clin Immunol. 2006;6:51–55. [PubMed]
24. Wilson J. The bronchial microcirculation in asthma. Clin Exp Allergy. 2000;30(Suppl 1):51–53. [PubMed]
25. Bates DV. Respiratory Function in Disease. 1. W.B. Saunders; Philadelphia: 1971.
26. Lee SY, Kwon S, Kim KH, Moon HS, Song JS, Park SH, et al. Expression of vascular endothelial growth factor and hypoxia-inducible factor in the airway of asthmatic patients. Ann Allergy Asthma Immunol. 2006;97:794–799. [PubMed]
27. Zanini A, Chetta A, Saetta M, Baraldo S, D’Ippolito R, Castagnaro A, et al. Chymase-positive mast cells play a role in the vascular component of airway remodeling in asthma. J Allergy Clin Immunol. 2007;120:329–333. [PubMed]
28. Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Choe YH, et al. Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1alpha-VEGF axis. Am J Respir Crit Care Med. 2008;178:787–797. [PubMed]
29. Hasaneen NA, Zucker S, Lin RZ, Vaday GG, Panettieri RA, Foda HD. Angiogenesis is induced by airway smooth muscle strain. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1059–L1068. [PubMed]
30. McDonald DM. Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med. 2001;164(10 Pt 2):S39–S45. [PubMed]
31. Baluk P, Lee CG, Link H, Ator E, Haskell A, Elias JA, et al. Regulated angiogenesis and vascular regression in mice overexpressing vascular endothelial growth factor in airways. Am J Pathol. 2004;165:1071–1085. [PubMed]
32. Simcock DE, Kanabar V, Clarke GW, O’Connor BJ, Lee TH, Hirst SJ. Proangiogenic activity in bronchoalveolar lavage fluid from patients with asthma. Am J Respir Crit Care Med. 2007;176:146–153. [PubMed]
33. Mitsuyama H, Matsuyama W, Iwakawa J, Higashimoto I, Watanabe M, Osame M, et al. Increased serum vascular endothelial growth factor level in Churg-Strauss syndrome. Chest. 2006;129:407–411. [PubMed]
34. Ye YM, Kang YM, Kim SH, Kim CW, Kim HR, Hong CS, et al. Relationship between neurokinin 2 receptor gene polymorphisms and serum vascular endothelial growth factor levels in patients with toluene diisocyanate-induced asthma. Clin Exp Allergy. 2006;36:1153–1160. [PubMed]
35. Bhandari V, Choo-Wing R, Chapoval SP, Lee CG, Tang C, Kim YK, et al. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci USA. 2006;103:11021–11026. [PubMed]
36. Bhandari V, Choo-Wing R, Lee CG, Yusuf K, Nedrelow JH, Ambalavanan N, et al. Developmental regulation of NO-mediated VEGF-induced effects in the lung. Am J Respir Cell Mol Biol. 2008;39:420–430. [PMC free article] [PubMed]
37. El-Chemaly S, Levine SJ, Moss J. Lymphatics in lung disease. Ann NY Acad Sci. 2008;1131:195–202. [PMC free article] [PubMed]
38. Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med. 2008;14:633–640. [PMC free article] [PubMed]
39. Sidorchuk A, Wickman M, Pershagen G, Lagarde F, Linde A. Cytomegalovirus infection and development of allergic diseases in early childhood: interaction with EBV infection? J Allergy Clin Immunol. 2004;114:1434–1440. [PubMed]
40. Hashimoto S, Matsumoto K, Gon Y, Ichiwata T, Takahashi N, Kobayashi T. Viral infection in asthma. Allergol Int. 2008;57:21–31. [PubMed]
41. Leigh R, Oyelusi W, Wiehler S, Koetzler R, Zaheer RS, Newton R, et al. Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling. J Allergy Clin Immunol. 2008;121:1238–1245. [PubMed]
42. Kilani MM, Mohammed KA, Nasreen N, Tepper RS, Antony VB. RSV causes HIF-1alpha stabilization via NO release in primary bronchial epithelial cells. Inflammation. 2004;28:245–251. [PubMed]
43. Haeberle HA, Durrstein C, Rosenberger P, Hosakote YM, Kuhlicke J, Kempf VA, et al. Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection. PLoS ONE. 2008;3:e3352. [PMC free article] [PubMed]
44. Wakisaka N, Murono S, Yoshizaki T, Furukawa M, Pagano JS. Epstein-Barr virus latent membrane protein 1 induces and causes release of fibroblast growth factor-2. Cancer Res. 2002;62:6337–6344. [PubMed]
45. Rydell-Tormanen K, Johnson JR, Fattouh R, Jordana M, Erjefalt JS. Induction of vascular remodeling in the lung by chronic house dust mite exposure. Am J Respir Cell Mol Biol. 2008;39:61–67. [PubMed]
46. Avdalovic MV, Putney LF, Schelegle ES, Miller L, Usachenko JL, Tyler NK, et al. Vascular remodeling is airway generation-specific in a primate model of chronic asthma. Am J Respir Crit Care Med. 2006;174:1069–1076. [PMC free article] [PubMed]
47. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008;453:807–811. [PMC free article] [PubMed]
48. Zinkernagel AS, Johnson RS, Nizet V. Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med. 2007;85:1339–1346. [PubMed]
49. Chachami G, Hatziefthimiou A, Liakos P, Ioannou MG, Koukoulis GK, Bonanou S, et al. Exposure of differentiated airway smooth muscle cells to serum stimulates both induction of hypoxia-inducible factor-1{alpha} and airway responsiveness to ACh. Am J Physiol Lung Cell Mol Physiol. 2007;293:L913–L922. [PubMed]
50. Anand RJ, Gribar SC, Li J, Kohler JW, Branca MF, Dubowski T, et al. Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1alpha-dependent manner. J Leukoc Biol. 2007;82:1257–1265. [PubMed]
51. Li W, Petrimpol M, Molle KD, Hall MN, Battegay EJ, Humar R. Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2. Circ Res. 2002;100:79–87. [PubMed]
52. Cramer T, Schipani E, Johnson RS, Swoboda B, Pfander D. Expression of VEGF isoforms by epiphyseal chondrocytes during low-oxygen tension is HIF-1 alpha dependent. Osteoarthritis Cartilage. 2004;12:433–439. [PubMed]
53. Welford SM, Bedogni B, Gradin K, Poellinger L, Broome Powell M, Giaccia AJ. HIF-1α delays premature senescence through the activation of MIF. Genes Dev. 2006;20:3366–3371. [PubMed]
54. Okuyama H, Krishnamachary B, Zhou YF, Nagasawa H, Bosch-Marce M, Semenza GL. Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1. J Biol Chem. 2006;281:15554–15563. [PubMed]
55. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passesgué E, et al. HIF-1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206–220. [PMC free article] [PubMed]
56. Bosch-Marce M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res. 2007;101:1310–1318. [PubMed]
57. Feng W, Ye F, Xue W, Zhou Z, Kang YJ. Copper regulation of hypoxia-inducible factor-1 activity. Mol Pharmacol. 2008;75:174–182. [PubMed]
58. Kennedy T, Ghio AJ, Reed W, Samet J, Zagorski J, Carter J, et al. Copper-dependent inflammation and nuclear factor-kappab activation by particulate air pollution. Am J Respir Cell Mol Biol. 1998;19:366–378. [PubMed]
59. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clinic Invest. 2007;117:3810–3820. [PMC free article] [PubMed]
60. Kimura K, Iwano M, Higgins DF, Yamaguchi Y, Nakatani K, Harada K, et al. Stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol. 2008;295:F1023–F1029. [PubMed]
61. Vural H, Uzun K, Uz E, Kocyigit A, Cigli A, Akyol O. Concentrations of copper, zinc and various elements in serum patients with bronchial asthma. J Trace Elem Med Biol. 2000;14:88–91. [PubMed]
62. Torre O, Olivieri D, Barnes PJ, Kharitonov SA. Feasibility and interpretation of FE(NO) measurements in asthma patients in general practice. Respir Med. 2008;102:1417–1424. [PubMed]
63. Moore WC. Update in asthma 2007. Am J Respir Crit Care Med. 2008;177:1068–1073. [PubMed]
64. Berchner-Pfannschmidt U, Yamac H, Trinidad B, Fandrey J. Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2. J Biol Chem. 2007;282:1788–1796. [PubMed]
65. Leuwerke SM, Kaza AK, Tribble CG, Kron IL, Laubach VE. Inhibition of compensatory lung growth in endothelial nitric oxide synthase-deficient mice. Am J Physiol Lung Cell Mol Physiol. 2002;282:L1272–L1278. [PubMed]
66. Catalli AE, Thomson JV, Babirad IM, Duong M, Doyle TM, Howie KJ, et al. Modulation of beta1-integrins on hemopoietic progenitor cells after allergen challenge in asthmatic subjects. J Allergy Clin Immunol. 2008;122:803–810. [PubMed]
67. Dorman SC, Babirad I, Post J, Watson RM, Foley R, Jones GL, et al. Progenitor egress from the bone marrow after allergen challenge: role of stromal cell-derived factor 1alpha and eotaxin. J Allergy Clin Immunol. 2005;115:501–507. [PubMed]
68. Parameswaran K, Watson R, Gauvreau GM, Sehmi R, O’Byrne PM. The effect of pranlukast on allergen-induced bone marrow eosinophilopoiesis in subjects with asthma. Am J Respir Crit Care Med. 2004;169:915–920. [PubMed]
69. Asosingh K, Swaidani S, Aronica M, Erzurum SC. Th1- and Th2-dependent endothelial progenitor cell recruitment and angiogenic switch in asthma. J Immunol. 2007;178:6482–6494. [PubMed]
70. Ben S, Li X, Xu F, Xu W, Li W, Wu Z, et al. Treatment with anti-CC chemokine receptor 3 monoclonal antibody or dexamethasone inhibits the migration and differentiation of bone marrow CD34 progenitor cells in an allergic mouse model. Allergy. 2008;63:1164–1176. [PubMed]
71. Menzies-Gow AN, Flood-Page PT, Robinson DS, Kay AB. Effect of inhaled interleukin-5 on eosinophil progenitors in the bronchi and bone marrow of asthmatic and non-asthmatic volunteers. Clin Exp Allergy. 2007;37:1023–1032. [PubMed]
72. Nakae S, Suto H, Berry GJ, Galli SJ. Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice. Blood. 2007;109:3640–3648. [PubMed]
73. Reuter S, Heinz A, Sieren M, Wiewrodt R, Gelfand EW, Stassen M, et al. Mast cell-derived tumour necrosis factor is essential for allergic airway disease. Eur Respir J. 2008;31:773–782. [PubMed]
74. Gomperts BN, Strieter RM. Fibrocytes in lung disease. J Leukoc Biol. 2007;82:449–456. [PubMed]
75. Nihlberg K, Larsen K, Hultgardh-Nilsson A, Malmstrom A, Bjermer L, Westergren-Thorsson G. Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane? Respir Res. 2006;7:50. [PMC free article] [PubMed]
76. Blanchet MR, Maltby S, Haddon DJ, Merkens H, Zbytnuik L, McNagny KM. CD34 facilitates the development of allergic asthma. Blood. 2007;110:2005–2012. [PubMed]
77. Taranova AG, Maldonado D, III, Vachon CM, Jacobsen EA, bdala-Valencia H, McGarry MP, et al. Allergic pulmonary inflammation promotes the recruitment of circulating tumor cells to the lung. Cancer Res. 2008;68:8582–8589. [PMC free article] [PubMed]
78. Uhlig S, Gulbins E. Sphingolipids in the lungs. Am J Respir Crit Care Med. 2008;178:1100–1114. [PubMed]
79. Ryan JJ, Spiegel S. The role of sphingosine-1-phosphate and its receptors in asthma. Drug News Perspect. 2008;21:89–96. [PMC free article] [PubMed]
80. Rivera J, Proia RL, Olivera A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 2008;8:753–763. [PMC free article] [PubMed]
81. Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, et al. Sphingosine 1 phosphate promotes endothelial cell barriar integrity by Edg dependent cytoskeletal rearrangement. J Clin Invest. 2001;108:689–701. [PMC free article] [PubMed]
82. Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T. Induction of vascular permeability by the sphingosine 1 phosphate receptor 2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol. 2007;27:1312–1318. [PubMed]
83. Waeber C, Blondeau N, Salomone S. Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Drug News Perspect. 2004;17:365–382. [PubMed]
84. Xie B, Shen J, Dong A, Rashid A, Stoller G, Campochiaro PA. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol. 2009;218:192–198. [PMC free article] [PubMed]
85. Tanimoto T, Jin ZG, Berk BC. Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS) J Biol Chem. 2002;277:42997–43001. [PubMed]
86. Kume H, Takeda N, Oguma T, Ito S, Kondo M, Ito Y, et al. Sphingosine 1-phosphate causes airway hyper-reactivity by rho-mediated myosin phosphatase inactivation. J Pharmacol Exp Ther. 2007;320:766–773. [PubMed]
87. Lai WQ, Goh HH, Bao Z, Wong WS, Melendez AJ, Leung BP. The role of sphingosine kinase in a murine model of allergic asthma. J Immunol. 2008;180:4323–4329. [PubMed]
88. Nishiuma T, Nishimura Y, Okada T, Kuramoto E, Kotani Y, Jahangeer S, et al. Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1085–L1093. [PubMed]
89. Linz-McGillem LA, Moitra J, Garcia JG. Cytoskeletal rearrangement and caspase activation in sphingosine 1-phosphate-induced lung capillary tube formation. Stem Cells Dev. 2004;13:496–508. [PubMed]
90. Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60:181–195. [PMC free article] [PubMed]
91. Igarashi J, Erwin PA, Dantas AP, Chen H, Michel T. VEGF induces S1P1 receptors in endothelial cells: implications for cross-talk between sphingolipid and growth factor receptors. Proc Natl Acad Sci USA. 2003;100:10664–10669. [PubMed]
92. Martin F, Linden T, Katschinski DM, Oehme F, Flamme I, Mukhopadhyay CK, et al. Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood. 2005;105:4613–4619. [PubMed]
93. Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine-1-phosphate. Curr Opin Pharmacol. 2006;6:244–250. [PubMed]
94. Morris CR, Polijakovic M, Lavrisha L, Machado L, Kuypers FA, Morris SM., Jr Decreased arginine bioavailability and increased serum arginase activity in asthma. Am J Respir Crit Care Med. 2004;170:148–153. [PubMed]
95. Venkataraman K, Lee YM, Michaud J, Thangada S, Ai Y, Bonkovsky HL, et al. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ Res. 2008;102:669–676. [PMC free article] [PubMed]
96. Petrache I, Natarajan I, Zhen L, Medler TR, Richter AT, Cho C, et al. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med. 2005;11:491–498. [PMC free article] [PubMed]
97. Kanazawa H. Microvascular theory of exercise-induced bronchoconstriction in asthma: potential implication of vascular endothelial growth factor. Inflamm Allergy Drug Targets. 2007;6:133–137. [PubMed]
98. Schwalm S, Doll F, Romer I, Bubnova S, Pfeilschifter J, Huwiler A. Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells. Biochem Biophys Res Commun. 2008;368:1020–1025. [PubMed]
99. Walczak-Drzewiecka A, Ratajewski M, Wagner W, Dastych J. HIF-1α is up-regulated in activated mast cells by a process that involves calcineurin and NFAT. J Immunol. 2008;181:1665–1672. [PubMed]
100. Jantsch J, Charkravortty D, Turza N, Prechtel AT, Buchholz B, Gerlach RG, et al. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol. 2008;180:4697–4705. [PubMed]
101. Pajusola K, Kunnapuu J, Vuorikoski S, Soronen J, Andre H, Pereira T, et al. Stablized HIF-1alpha is superior to VEGF for angiogenesis in skeletal muscle via adeno-associated virus gene transfer. FASEB J. 2005;19:1365–1367. [PubMed]
102. McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol. 2004;172:2903–2908. [PubMed]
103. Kim DY, Ryu SY, Lim JE, Lee YS, Ro JY. Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model. Eur J Pharmacol. 2007;557:76–86. [PubMed]
104. Loboda A, Jazwa A, Jozkowicz A, Molema G, Dulak J. Angiogenic transcriptome of human microvascular endothelial cells: effect of hypoxia, modulation by atorvastatin. Vascul Pharmacol. 2006;44:206–214. [PMC free article] [PubMed]