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Advances in mechanisms of asthma, allergy, and immunology in 2008

2009; Elsevier BV; Volume: 123; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2009.01.041

1097-6825

Joshua A. Boyce, David H. Broide, Kenji Matsumoto, Bruce S. Bochner,

Respiratory and Cough-Related Research

This review summarizes selected articles appearing in 2008 in the Journal. Articles chosen include those improving our understanding of mechanisms of allergic diseases by focusing on human basophil, mast cell, and eosinophil biology; IgE and its high-affinity receptor on various cells; novel properties of omalizumab; airways remodeling; and genetics. Articles from other journals have been included to supplement the topics presented. This review summarizes selected articles appearing in 2008 in the Journal. Articles chosen include those improving our understanding of mechanisms of allergic diseases by focusing on human basophil, mast cell, and eosinophil biology; IgE and its high-affinity receptor on various cells; novel properties of omalizumab; airways remodeling; and genetics. Articles from other journals have been included to supplement the topics presented. The JACI is one of the premier journals for publication of human cell biology and genetics relevant to asthma and allergic diseases, and this past year was no exception. Studies published in 2008 have advanced our knowledge regarding pathways controlling degranulation of IgE receptor bearing cells and have further elucidated the ability of IgE and anti-IgE therapies to modulate cellular responses. The list of mechanisms by which eosinophils can be activated and kept alive was expanded, as was the list of mechanisms by which viruses, cytokines, and other agents may contribute to expression of remodeling genes in the airway. Murine studies explored the potential of immunomodulator therapies to influence airway remodeling. Additional studies furthered our understanding of genes related to atopic disorders including asthma, especially those involved in innate immune responses (Table 1).Table 1Key advances in mechanisms of asthma, allergy, and immunology in 20081.For mast cell and basophil biology, advances include involvement and antagonism (by novel molecules and curcumin) of Syk kinase in FcεRI signaling; inhibition of FcεRI signaling by Siglec-8; role of adenosine A3 receptors and activated T-cell surface molecules in mast cell activation; contribution of serglycin to mast cell granule storage function; evolution of mast cell proteases across species.2.For IgE biology, advances include comparison of clinical assays for measuring specific IgE; characterization of multiple functional properties of IgE affecting affinity for ligand and degranulation responses in basophils.3.For omalizumab, advances include effects on free IgE levels and skin test responses over time; effects on asthma and tissue eosinophilia in a patient developing Churg-Strauss syndrome while receiving omalizumab; benefits in autoimmune urticaria.4.Eosinophils: activating activity of IL-33 via its receptor ST2; ability of extracellular cationic charges to enhance eosinophil degranulation; report of a patient with chronic eosinophilic leukemia manifesting resistance to imatinib caused by mutations in the FIP1L1-PDGFRA kinase domain.5.Airway remodeling and AHR in asthma: causative contributions of rhinovirus, VEGF, sADAM33, and mast cells within airway smooth muscle; use of DCregs to reduce AHR in mice; inhibitory effect of corticosteroids on cysteinyl leukotriene receptor expression on leukocytes incubated with IL-4.6.Genetics of allergic diseases: influence of polymorphisms in innate immune receptors including TLRs and filaggrin on asthma and atopic dermatitis by altering both adjuvant effects of microbial agents and local responses to viral and bacterial infections. Open table in a new tab Spleen-type (Syk) tyrosine kinase is required for the activation of mast cells and basophils occurring in response to FcεRI cross-linkage. Mazuc et al1Mazuc E. Villoutreix B.O. Malbec O. Roumier T. Fleury S. Leonetti J.P. et al.A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally.J Allergy Clin Immunol. 2008; 122: 188-194Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar used an ingenious strategy to identify a novel Syk inhibitor. These investigators had previously reported that an antibody (termed G4G11) directed against an amino acid sequence that is conserved among the Src homology 2 (Sh2) domains of human, mouse, and rat Syk, introduced into RBL-2H3 cells (a rat mast cell line), blocks FcεRI-mediated activation.2Dauvillier S. Merida P. Visintin M. Cattaneo A. Bonnerot C. Dariavach P. Intracellular single-chain variable fragments directed to the Src homology 2 domains of Syk partially inhibit Fc epsilon RI signaling in the RBL-2H3 cell line.J Immunol. 2002; 169: 2274-2283PubMed Google Scholar The investigators screened an extensive panel of small molecules for their ability to displace G4G11 from its target epitope.1Mazuc E. Villoutreix B.O. Malbec O. Roumier T. Fleury S. Leonetti J.P. et al.A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally.J Allergy Clin Immunol. 2008; 122: 188-194Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar They identified 15 molecules that displaced G4G11 binding, and tested 1 of these (termed C-13) for the ability to block Syk-mediated activation of mast cells. These investigators determined that C-13 binding required Arg68, Glu121, and Glu155 of Syk. C-13 was cell-permeable and blocked FcεRI-mediated activation of RBL-2H3 cells by preventing Syk-dependent phosphorylation of Bruton tyrosine kinase (Btk) and several downstream signaling events. Orally administered C-13 blocked both passive cutaneous and systemic anaphylaxis in mice. This study is an exciting step in the development of Syk-targeted drugs for allergic diseases. Curcumin (a pigment of curry powder) was previously reported to have anti-allergic properties in animal models of allergy.3Ju H.R. Wu H.Y. Nishizono S. Sakono M. Ikeda I. Sugano M. et al.Effects of dietary fats and curcumin on IgE-mediated degranulation of intestinal mast cells in brown Norway rats.Biosci Biotechnol Biochem. 1996; 60: 1856-1860Crossref PubMed Scopus (24) Google Scholar Lee et al4Lee J.H. Kim J.W. Ko N.Y. Mun S.H. Her E. Kim B.K. et al.Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk.J Allergy Clin Immunol. 2008; 121: 1225-1231Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar showed that treatment of RBL-2H3 cells with curcumin inhibited their FcεRI-mediated degranulation, production of both TNF-α and IL-4, and activation of mitogen-activated protein kinase. Like C-13, curcumin inhibited Syk enzymatic activity without blocking its FcεRI-mediated phosphorylation. Although it is not known whether curcumin targets a region of Syk that is similar to that bound by C-13, this study once again highlights the therapeutic potential of interference with Syk in allergic disease. Syk is transiently inactivated after FcεRI-mediated cell activation, resulting in a refractory period during which mast cells or basophils are resistant to a second activation after cross-linkage of FcεRI. MacGlashan and Undem5MacGlashan Jr., D. Undem B.J. Inducing an anergic state in mast cells and basophils without secretion.J Allergy Clin Immunol. 2008; 121: 1500-1506Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar demonstrated that a Syk inhibitor (NVP-QAB205) completely blocked the release of mediators by mast cells challenged with anti-IgE but had no effect on Syk inactivation (as indicated by the lack of mediator release in response to a second stimulation with anti-IgE).6Yokoi H. Choi O.H. Hubbard W. Lee H.S. Canning B.J. Lee H.H. et al.Inhibition of FcepsilonRI-dependent mediator release and calcium flux from human mast cells by sialic acid-binding immunoglobulin-like lectin 8 engagement.J Allergy Clin Immunol. 2008; 121: 499-505Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar A similar result was obtained with basophils. An inhibitor of phospatidylinostol-3-phosphate kinase (PI-3K) also completely blocked mediator release by anti-IgE–activated basophils without altering inactivation of Syk. Thus, neither Syk activation nor PI-3K activity is necessary for the transient inactivation of Syk after mast cell or basophil activation. These findings suggest that pharmacologic antagonists that target either Syk or PI-3K should block anaphylactic mediator release without interfering with the potentially desired effect of Syk inactivation during desensitization to antigen. Sialic acid–binding immunoglobulin-like lectins (Siglecs) are a family of receptors that bind to extracellular glycan structures. Many Siglecs are predicted to have inhibitory functions based on the presence of immunoreceptor tyrosine inhibitory motifs. One member of this family, Siglec-8, is selectively expressed on human eosinophils, basophils, and mast cells. Yokoi et al6Yokoi H. Choi O.H. Hubbard W. Lee H.S. Canning B.J. Lee H.H. et al.Inhibition of FcepsilonRI-dependent mediator release and calcium flux from human mast cells by sialic acid-binding immunoglobulin-like lectin 8 engagement.J Allergy Clin Immunol. 2008; 121: 499-505Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar demonstrated that Siglec-8 engagement inhibited exocytosis by human mast cells in vitro, as well as their production of prostaglandin D2, but not release of IL-8. Siglec-8 engagement also inhibited the contraction of isolated human bronchi in response to stimulation with anti-IgE. The authors generated a series of mutated Siglec-8 constructs, and demonstrated in RBL-2H3 cells that the immunoreceptor tyrosine inhibitory motif domain was crucial for the inhibitory function of Siglec-8. Thus, antibodies or molecules that mimic Siglec-8 ligands could be developed as potential therapeutic agents that prevent mediator generation by mast cells and its physiologic consequences. Adenosine, a product of neurons and vascular cells released in response to stress, hypoxia, and inflammation, is a known agonist of mast cell activation in vitro, and induces bronchoconstriction by a mechanism that depends on mast cell–derived mediators. Hua et al7Hua X. Chason K.D. Fredholm B.B. Deshpande D.A. Penn R.B. Tilley S.L. Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells.J Allergy Clin Immunol. 2008; 122: 107-113Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar studied the potential role of adenosine in mediating airway hyperresponsiveness (AHR) to methacholine. Inhalation of the stable adenosine analogue adenosine-5′ N-ethylcarboxamide induced AHR in mice. This feature was absent in mast cell–deficient Wsh/Wsh mice, as well as in mice lacking the A3-type adenosine receptor. The direct role of A3 receptors on mast cells was confirmed by adoptive transfer experiments, in which engraftment of the Wsh/Wsh mice with mast cells derived from wild-type mice, but not with mast cells derived from A3 receptor–deficient mice, restored AHR after inhalation of adenosine-5′ N-ethylcarboxamide. The adenosine pathway may thus be an important IgE-independent mechanism by which mast cells contribute to AHR. Salamon et al8Salamon P. Shoham N.G. Puxeddu I. Paitan Y. Levi-Schaffer F. Mekori Y.A. Human mast cells release oncostatin M on contact with activated T cells: possible biologic relevance.J Allergy Clin Immunol. 2008; 121: 448-455Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar used a microarray to identify the profile of mRNA transcripts inducibly expressed by the human LAD2 mast cell line when these cells were incubated in the presence of membranes derived from activated T cells. This condition induced the expression of 200 transcripts that were not expressed in response to FcεRI cross-linkage. These included several cytokines and chemokines, such as oncostatin M, a cytokine belonging to the IL-6 family with profibrotic properties. LAD2 cells and cord blood–derived mast cells secreted oncostatin M protein when incubated with membranes from activated but not from resting T cells. The production of oncostatin M was sensitive to dexamethasone and could also be modestly suppressed by curcumin. The quantities of oncostatin M secreted by mast cells were sufficient to induce the proliferation of fibroblasts in vitro. Thus, oncostatin M, produced by mast cells in response to contact with activated T cells, may promote remodeling of the airway and other tissues. Mast cells and basophils store preformed histamine (and mouse mast cells also store serotonin) in secretory granules. Storage of these mediators involves proteoglycans that contain a core peptide termed serglycin. Ringvall et al9Ringvall M. Ronnberg E. Wernersson S. Duelli A. Henningsson F. Abrink M. et al.Serotonin and histamine storage in mast cell secretory granules is dependent on serglycin proteoglycan.J Allergy Clin Immunol. 2008; 121: 1020-1026Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar studied the storage of histamine and serotonin in mast cells from mice lacking serglycin. The granules of the mast cells from the serglycin knockout strain were poorly developed and contained less histamine and serotonin than did the mast cells from the wild-type strain, particularly in vivo. Although in vivo-derived and in vitro-derived mast cells from both strains released histamine and serotonin when activated by using calcium ionophore, the quantities released from the cells of the serglycin knockout mice were substantially lower. Interestingly, although release depended entirely on preformed stores, some of the serotonin released was synthesized de novo in response to cell activation. The ability of mast cells to generate serotonin, but not histamine, de novo in response to activation suggests a mechanism for the release of this important vasoactive substance that occurs independently of classic degranulation. Mouse mast cells express 2 functionally divergent tryptases, termed mouse mast cell protease (MMCP)–6, a homolog of human mast cell tryptase β, and MMCP-7. Human mast cell granules lack a true ortholog of MMCP-7, instead expressing small amounts of tryptase δ, an enzyme that does not exist in mice and that has weak protease activity. Trivedi et al10Trivedi N.N. Raymond W.W. Caughey G.H. Chimerism, point mutation, and truncation dramatically transformed mast cell delta-tryptases during primate evolution.J Allergy Clin Immunol. 2008; 121: 1262-1268Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar determined how tryptase δ changed during primate evolution, and why the human enzyme possesses such weak activity. All primates studied (including lemurs, macaque, and great apes) possess genes encoding tryptase δ, which evolved by transformation from an ancestral MMCP-7–like gene. The human tryptase δ gene is truncated, affecting its substrate-binding pocket, resulting in a loss of function. Interestingly, the truncation exists in the tryptase δ genes of the great apes, but not the lemur or macaque genes. Moreover, tryptase δ, and not tryptase β, is the major active tryptase in the monkeys. This study suggests that there were selective environmental pressures that caused the truncation of tryptase δ during the transition to higher primates. Wang et al11Wang J. Godbold J.H. Sampson H.A. Correlation of serum allergy (IgE) tests performed by different assay systems.J Allergy Clin Immunol. 2008; 121: 1219-1224Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar compared different clinical laboratory assays by their ability to quantitate allergen-specific IgE levels. They used 3 commercial assays to determine whether measurements of IgE were similar and found that there were obvious differences. For example, using the ImmunoCAP assays (Phadia, Uppsala, Sweden) as the standard for comparison, the Immulite 2000 system (Siemens Medical Solutions Diagnostics, Tarrytown, NY) tended to overestimate specific IgE levels, whereas the Turbo-MP assay (Agilent Technologies, Santa Clara, Calif) overestimated egg-specific IgE but underestimated dust mite and birch IgE. One important conclusion offered by the authors was that the predicted values previously generated with the ImmunoCAP assay for likelihood of clinical reactivity associated with food-specific IgE levels cannot automatically be applied to results of IgE measurements obtained by using other assays. Christensen et al12Christensen L.H. Holm J. Lund G. Riise E. Lund K. Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge.J Allergy Clin Immunol. 2008; 122: 298-304Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar developed a panel of 31 fully human or mouse-human chimeric recombinant IgEs specific for the house dust mite allergen Der p 2. They then investigated how individual properties of IgE affect biology. They also studied the affinity of these IgEs for Der p 2 and showed that these recombinant IgEs bound 9 different Der p 2 epitopes with affinities ranging widely from low picomolar to mid nanomolar. They discovered that enhanced basophil degranulation occurred with higher total IgE concentrations, with increased ratios of allergen-specific IgE relative to total IgE, with a more even concentration of individual allergen-specific IgE antibody types, with higher IgE affinity for the Der p 2 epitope, and with an increased number of Der p 2 epitopes recognized by the IgE. This landmark study, as pointed out by the accompanying editorial by Hamilton and Saito,13Hamilton R.G. Saito H. IgE antibody concentration, specific activity, clonality, and affinity measures from future diagnostic confirmatory tests.J Allergy Clin Immunol. 2008; 122: 305-306Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar showed comprehensively how IgE antibody concentration, IgE antibody clonality, specific activity, and affinity all influence degranulation responses, and helped us understand why IgE effects cannot simply be predicted by current specific IgE measurements. Several articles explored new interesting aspects of omalizumab therapy. Corren et al14Corren J. Shapiro G. Reimann J. Deniz Y. Wong D. Adelman D. et al.Allergen skin tests and free IgE levels during reduction and cessation of omalizumab therapy.J Allergy Clin Immunol. 2008; 121: 506-511Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar published work giving 2-fold to 4-fold higher intravenous doses of omalizumab than currently approved and then reducing the dosing after 28 weeks to see if such step-down dosing would allow beneficial effects to persist. After 14 weeks of administration of the higher dose of intravenous omalizumab, they observed a >95% suppression of serum free IgE concentrations. Dust mite skin prick tests were also markedly inhibited. When intravenous dosing was reduced, serum free IgE levels and allergen skin test reactivity increased significantly. Months after discontinuation of therapy, serum free IgE levels and skin test reactivity returned to pretreatment levels. Two key findings of this study were that (1) treatment of 6 to 12 months with omalizumab is unlikely to cause any persistent change in free IgE levels and skin test reactivity off omalizumab, and (2) reductions of omalizumab dosing may allow restoration of IgE-mediated responses. In a letter to the editor, Ruppert et al15Ruppert A.M. Averous G. Stanciu D. Deroide N. Riehm S. Poindron V. et al.Development of Churg-Strauss syndrome with controlled asthma during omalizumab treatment.J Allergy Clin Immunol. 2008; 121: 253-254Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar reported on an interesting case in which a 62-year-old man with chronic sinusitis and persistent asthma was treated with omalizumab. His asthma responded favorably, even as he was tapered off prednisolone, but later that year he developed Churg-Strauss syndrome. The omalizumab was stopped, and he was put back on oral steroids plus cyclophosphamide with improvement. As the authors commented, it is possible that the successful use of omalizumab to control the asthma permitted systemic steroid withdrawal and unmasking of an underlying diagnosis of Churg-Strauss syndrome. More indisputable in this 1 case is that omalizumab, in the absence of systemic steroids, was incapable of preventing the extensive tissue eosinophilia that developed in association with Churg-Strauss syndrome in this individual, even though omalizumab has been shown to reduce airway eosinophilia in patients with asthma.16Djukanovic R. Wilson S.J. Kraft M. Jarjour N.N. Steel M. Chung K.F. et al.Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma.Am J Respir Crit Care Med. 2004; 170: 583-593Crossref PubMed Scopus (550) Google Scholar Finally, Kaplan et al17Kaplan A.P. Joseph K. Maykut R.J. Geba G.P. Zeldin R.K. Treatment of chronic autoimmune urticaria with omalizumab.J Allergy Clin Immunol. 2008; 122: 569-573Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar reported on a study of omalizumab for the treatment of chronic urticaria with autoimmune features. Twelve patients manifesting serum-induced in vitro basophil histamine release and autologous skin test responses were treated with placebo for 4 weeks followed by omalizumab for 16 weeks. Marked improvement in urticaria symptom scores was observed, with 7 patients achieving complete resolution, 4 showing improvement, and 1 showing no improvement whatsoever. The treatment was well tolerated. These exciting findings have apparently been confirmed in a slightly larger placebo-controlled trial.18Vonakis B.M. Saini S.S. New concepts in chronic urticaria.Curr Opin Immunol. 2008; 20: 709-716Crossref PubMed Scopus (98) Google Scholar Cherry et al19Cherry W.B. Yoon J. Bartemes K.R. Iijima K. Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils.J Allergy Clin Immunol. 2008; 121: 1484-1490Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar added to the list of known cytokines capable of activating human eosinophils and prolonging their survival by showing that IL-33, a member of the IL-1 cytokine family, can cause production of superoxide anion, eosinophil degranulation, and enhanced survival as effectively as IL-5. Receptors for IL-33, namely ST2, were detected on eosinophils, and IL-33–induced survival and production of IL-8 were all blocked with an antibody to ST2. Therefore, IL-33, which is produced by structural cells such as airway epithelium and promotes survival and cytokine production by human mast cells, should gain more attention as a potential contributor to allergic cellular responses. Adamko et al20Adamko D.J. Wu Y. Ajamian F. Ilarraza R. Moqbel R. Gleich G.J. The effect of cationic charge on release of eosinophil mediators.J Allergy Clin Immunol. 2008; 122: 383-390Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar explored how eosinophil activation may be influenced by cationic charge. They established an in vitro model to mimic cationic-charged deposition of eosinophil proteins in tissues by coating Sepharose beads with cationic or anionic substances. In the presence of eosinophil-activating cytokines, they showed that positively charged beads uniquely caused greater eosinophil degranulation. This release was a result of metabolic pathways such as those involving tyrosine phosphorylation and cyclic AMP because pharmacologic inhibitors of these pathways blocked responses. An additional mechanism involved appears to be clustering of β2 integrins on the eosinophils, where they adhered to the beads. It was concluded that exposure of eosinophils to positively charged surfaces in the presence of activating cytokines, as might occur in vivo at sites of chronic allergic inflammation, could enhance eosinophil degranulation. In a letter to the editor, Simon et al21Simon D. Salemi S. Yousefi S. Simon H.U. Primary resistance to imatinib in Fip1-like 1-platelet-derived growth factor receptor alpha-positive eosinophilic leukemia.J Allergy Clin Immunol. 2008; 121: 1054-1056Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar report on a 59-year-old man with Fip1-like1–platelet-derived growth factor receptor α-chain (FIP1L1-PDGFRA)—positive hypereosinophilic syndrome, also referred to as chronic eosinophilic leukemia. Unfortunately, he failed to respond to treatment with prednisone, IFN-α, hydroxyurea, or imatinib. He had an elevated serum IL-5 level, yet failed to respond to anti–IL-5 antibody (mepolizumab) used alone or in combination with imatinib, and ultimately died of heart failure. When the authors sequenced his FIP1L1-PDGFRA gene, they identified 2 mutations resulting in 2 amino acid changes within the kinase domain, which likely caused the imatinib resistance. This case report underscores the need for additional tyrosine kinase inhibitors that may prove effective even when imatinib resistance appears. Indeed, several such tyrosine kinase inhibitors are in advanced clinical trials.22Simon H.U. Cools J. Novel approaches to therapy of hypereosinophilic syndromes.Immunol Allergy Clin North Am. 2007; 27: 519-527Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Although the structural features of airway remodeling in asthma are well described, less is known about the mechanism by which environmental stimuli and genes interact to induce airway remodeling, particularly in the subset of patients with asthma with more severe airway remodeling and an increased rate of decline in lung function.23Broide D.H. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling.J Allergy Clin Immunol. 2008; 121: 560-570Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar Rhinovirus infections are the most frequent precipitant of asthma exacerbations triggered by viruses, but whether they contribute to airway remodeling is currently unknown. Because an increased frequency of asthma exacerbations may contribute to a more rapid decline in lung function,24O'Byrne P.M. Pedersen S. Lamm C.J. Tan W.C. Busse W.W. Severe exacerbations and decline in lung function in asthma.Am J Respir Crit Care Med. 2009; 179: 19-24Crossref PubMed Scopus (323) Google Scholar studies by Leigh et al25Leigh R. Oyelusi W. Wiehler S. Koetzler R. Zaheer R.S. 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: 1238-1245Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar investigated potential mechanisms by which rhinovirus infection may contribute to airway remodeling in asthma. They demonstrate that rhinovirus infection induces expression of vascular endothelial growth factor (VEGF), a proangiogenic cytokine, by airway epithelial cells in vitro. In addition, in healthy subjects with natural rhinovirus infection, levels of VEGF were increased in nasal lavage fluid at the time of peak symptoms compared with levels observed 4 weeks after the resolution of symptoms.25Leigh R. Oyelusi W. Wiehler S. Koetzler R. Zaheer R.S. 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: 1238-1245Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Although there was an increase in nasal lavage VEGF levels in healthy subjects, further studies are needed to determine whether subjects with asthma and rhinovirus infection have increased levels of VEGF (and possibly other proremodeling mediators) in the lower airway, and whether levels of VEGF associate with levels of airway angiogenesis or other features of airway remodeling. Interestingly, overexpression of VEGF in the airways of mice results in both airway angiogenesis and other features of airway remodeling,26Lee C.G. Link H. Baluk P. Homer R.J. Chapoval S. Bhandari V. et al.Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung.Nat Med. 2004; 10: 1095-1103Crossref PubMed Scopus (492) Google Scholar suggesting that expression of VEGF in asthma may contribute to more than 1 feature of airway remodeling in asthma. Single nucleotide polymorphisms in the metalloprotease a disintegrin and metalloprotease (ADAM)–33 have been linked with bronchial hyperresponsiveness, poor lung function in early childhood, and a more rapid decline in lung function in chronic obstructive pulmonary disease as well as in a healthy population.27Puxeddu I. Pang Y.Y. Harvey A. Haitchi H.M. Nicholas B. Yoshisue H. et al.The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: implications for airway remodeling in asthma.J Allergy Clin Immunol. 2008; 121: 1400-1406Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 28Van Eerdewegh P. Little R.D. Dupuis J. Del Mastro R.G. Falls K. Simon J. et al.Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.Nature. 2002; 418: 426-430Crossref PubMed Scopus (945) Google Scholar Initial studies demonstrated that ADAM33 was expressed by mesenchymal cells such as fibroblasts, myofibroblasts, and smooth muscle cells, but not by epithelial cells, suggesting that these lung cells would mediate the effects of ADAM33 on lung function in asthma. Subsequent studies suggested that airway epithelial cells were a source of ADAM33 in severe asthma.29Lee J.Y. Park S.W. Chang H.K. Kim H.Y. Rhim T. Lee J.H. et al.A disintegrin and metalloproteinase 33 protein in patients with asthma: relevance to airflow limitation.Am J Respir Crit Care Med. 2006; 173: 729-735Crossref PubMed Scopus (98) Google Scholar, 30Foley S.C. Mogas A.K. Olivenstein R. F