The cellular and mediator basis of asthma in relation to natural history
1997; Elsevier BV; Volume: 350; Linguagem: Inglês
10.1016/s0140-6736(97)90029-5
ISSN1474-547X
Autores Tópico(s)T-cell and B-cell Immunology
ResumoIt has long been known that asthma and atopy run in families, the heritability being estimated to be between 40% and 60%. Atopy is the single strongest risk factor for the development of asthma, increasing the risk by lo-20 fold compared with those who are non-atopic. Candidate and whole human genome searches have identified a number of possible gene linkages to asthma (table).1Holgate ST Asthma genetics: waiting to exhale.Nat Genet. 1997; 15: 227-229Crossref PubMed Scopus (77) Google Scholar, 2Daniels SE Bhattacharrya S James A et al.A genome-wide search for quantitative trait loci underlying asthma.Nature. 1996; 383: 247-250Crossref PubMed Scopus (699) Google Scholar Polymorphisms of the β2-adrenoceptor and the promoter regions of interleukin-4 (IL-4) and tumour necrosis factor a (TNFa) have been linked with increased disease severity. Susceptibility genes are also important at an allergen-specific level involving both MHC class II encoded on chromosome 6p and the a-chain of the T-cell receptor on chromosome 14q. Oligoclonal selection of T cells involved in the airway immune response, either in stable disease or following allergen exposure, is suggested by studies of the Vβ region of the T-cell receptor on cells recovered by lavage.3Burastero SE Crimi E Balbo A et al.Oligoclonality of lung T lymphocytes following exposure to allergen in asthma.J Immunol. 1995; 155: 5836-5846PubMed Google Scholar The complexities of genetic studies in asthma are only just being realised, with multiple genes and interactions involved and analyses confounded by multiple tests and lack of power. Progress is likely with the study of larger numbers of families, improvements in methods used to assess disease phenotype (eg, biomarkers of inflammation), more sophisticated methods for data analysis, and denser gene maps.1Holgate ST Asthma genetics: waiting to exhale.Nat Genet. 1997; 15: 227-229Crossref PubMed Scopus (77) Google ScholarTableCandidate genes and chromosomal regions in asthma and atopy for which positive linkage or association has been claimedChromosomal LocationCandidate(5)Function5q31IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSFCytokines upregulation IgE mast cell, basophil, and eosinophils functions5q32βT2adrenoceptor (polymorphisms 16 and 27)Bronchodilatation6pHLA complexAntigen presentation6p21·3TNFαL(polymorphisms eg, LtαLNcol)Pleiotropic inflammatory cytokine11q13Fc, RI (polymorphism E237G)Transduction signaling on mast cell, basophils, and dendritic cells12qInterferon-γMInhibition of Th2 cells12qConstitutive form of nitric oxide synthase, mast cell growth factorInflammatory mediators13qEsterase D protein?function14qT-cell receptor αL/γM complexT-cell activationGM-CSF=granulocyte macrophage colony-stimulating factor. Fct RI=high-affinity receptor for c3 domain of IgE. Open table in a new tab GM-CSF=granulocyte macrophage colony-stimulating factor. Fct RI=high-affinity receptor for c3 domain of IgE. Although asthma-specific genes are important, it is environmental factors that appear to further select the asthma phenotype. It is increasingly apparent that the atopic and possibly the asthma phenotype frequently begins early in life, even before birth.4Warner JA Jones AC Miles EA Colwell BM Warner JA Materno-fetal interaction and allergy.Allergy. 1996; 51: 447-451Crossref PubMed Scopus (49) Google Scholar In atopic children with recurrent wheezing illness, lavage studies reveal increased mast cell and eosinophil concentrations in children as young as 3 years. By 5 years of age, asthmatic children can be clearly separated from those with recurrent virus-induced wheeze in whom the neutrophil dominates.5Stevenson E, Turner G, Heaney LG, et al. Bronchoalveolar lavage findings suggest two different forms of childhood asthma. Clin Exp Allergy (in press).Google Scholar At birth and up to 11 years of age the peripheral blood mononuclear cell response to specific stimulation in children who develop atopic disease is deficient in its capacity to generate interferon-γ (IFN-γ), thereby causing upregulation of cytokines associated with a Th2 response and the allergic phenotype.6Warner JA Miles EA Jones AC Quint DJ Colwell BM Warner JA Is deficiency of interferon gamma production by allergen triggered cord blood T cells a predictor of atopic eczema?.Clin Exp Allergy. 1994; 24: 223-230Google Scholar, 7Tang MLK Kemp AS Thorburn J Hill DJ Reduced interferon-γ and subsequent atopy.Lancet. 1994; 344: 983-985Summary PubMed Scopus (391) Google Scholar The molecular basis for this defect is not known. It could involve impaired IL-12 or IL-18 production, the cytokines which regulate IFN-7, or a defect in the control of IIN-7 gene expression. Several groups have reported that T lymphocytes isolated from cord blood of babies born of atopic mothers are already able to respond to allergens including aeroallergens.8Miles EA Warner JA Jones AC Colwell BM Bryant TM Warner JO Peripheral blood mononuclear cell proliferation responses in the first year of life in babies born of allergic parents.Clin Exp Allergy. 1996; 26: 780-788Crossref PubMed Scopus (109) Google Scholar This remarkable finding suggests that low amounts of antigen taken in by the mother can be passed to her offspring via the placenta. The mechanisms involved are unknown, but appear to begin at 22–24 weeks of pregnancy. Fetal programming by the mother might explain several features that could contribute to the rising prevalences of allergy and asthma, including a link with cigarette smoking in pregnancy, the greater effect of maternal than paternal allergy on development of asthma in the offspring, and the positive association of head circumference at birth as an index of nutrition9Shaheen S Discovering the causes of atopy: patterns of childhood infection and fetal growth may be implicated.BMJ. 1997; 314: 987-988Crossref PubMed Scopus (25) Google Scholar It has been suggested that in vivo the immune environment of the fetus is directed towards a Th2 response as a result of IL-4 and IL-10 production by the amnion and placenta, and that predisposition towards asthma and associated allergic disorders results from a defect in the shutdown of this arm of the immune response by IL-12 and/or IFN-γ.10Holt PG Sly PD Allergic respiratory disease: strategic targets for primary prevention in childhood.Thorax. 1997; 52: 1-4Crossref PubMed Scopus (80) Google Scholar Although asthma may not be fully manifest until later childhood, exposure to allergen during the first 2–3 years appears important in providing the stimulus for local sensitisation of the lower airways.11Sporik R Holgate ST Platts-Mills TAE Cogswell JT Exposure to house dust mite allergen (Der P,) and the development of asthma in childhood: a prospective study.N Engl J Med. 1990; 323: 502-507Crossref PubMed Scopus (1421) Google Scholar It has been suggested that the first 3 years of life is a particularly critical time when environmental events may influence the development of the asthma phenotype.12Cookson WOCM Moffatt ME Asthma: an epidemic in the absence of infection.Science. 1997; 275: 41-42Crossref PubMed Scopus (272) Google Scholar There is some evidence that measles infection in the first year of life13Shaheen SO Aaby P Hall AJ et al.Measles and atopy in Guinea-Bissau.Lancet. 1996; 347: 1792-1796Summary PubMed Scopus (477) Google Scholar (and possibly other respiratory viruses) may protect against asthma and this might explain the inverse relation between socioeconomic status and asthma and allergy, 14Strachan DP Allergy and family size: a riddle worth solving.Clin Exp Allergy. 1997; 27: 235-236Crossref PubMed Scopus (98) Google Scholar the urban to rural decreasing gradient in asthma rates in developing countries, 15Strachan D Socioeconomic factors and the development of allergy.Toxcol Lett. 1996; 86: 199-203Crossref PubMed Scopus (45) Google Scholar and the substantial differences between the prevalence of asthma and other manifestations of allergy in eastern and western Europe related to separation of these two genetically similar populations by events after World War II.16Weichmann HE Environment, lifestyle and allergy: the German answer.Allergy. 1995; 4: 315-316Google Scholar From an immunological standpoint, frequent infection in early infancy causing high IL-12, IL-18, and IFN-γ production would lead to suppression of Th2 responses and unfavourable circumstances for allergen sensitisation.17Martinez FO Role of viral infections in the inception of asthma and allergies during childhood: could they be "protective"?.Thorax. 1994; 49: 1189-1191Crossref PubMed Scopus (226) Google Scholar The overuse of antibiotics, which might alter intestinal bacterial flora and reduce mucosal Thl responses (eg, preferential lactobacillus colonisation of the gut in eastern compared with western European infants, B Börjksten, personal communication), 10Holt PG Sly PD Allergic respiratory disease: strategic targets for primary prevention in childhood.Thorax. 1997; 52: 1-4Crossref PubMed Scopus (80) Google Scholar and the strong inverse association between the magnitude of a skin BCG response in Japanese 1-year-old children and the later development of asthma, are persuasive arguments in favour of the "hygiene hypothesis" (increasing asthma is due to decreasing infections in early life).18Shirakawa T Enomoto T Shimazu S-I Hopkin JM The inverse association between tuberculin responses and atopic disorder.Science. 1997; 275: 77-79Crossref PubMed Scopus (1161) Google Scholar Conversely, it has been suggested that respiratory syncytial virus infection is capable of augmenting a Th2 response in susceptible subjects, an observation that has been reproduced in a mouse model.19Hussell T Spender LC Georgiou A O'Garra A Openshaw PJM Th1 and Th2 cytokine induction in pulmonary T cells during infection with respiratory syncytial virus.J Gen Virol. 1996; 77: 2447-2455Crossref PubMed Scopus (141) Google Scholar Cohort studies in children of asthmatic and allergic parents, in which viruses are identified by gene-based methods, are needed to further examine these hypotheses. Sensitisation to food antigens such as ovalbumin and β-lactoglobulin in early life is associated with eczema. In general this manifestation of atopy usually diminishes after the age of 3–5 years with the acquisition of antigen-specific and non-specific tolerance leading to consolidation of a Th1 rather than a Th2 response.10Holt PG Sly PD Allergic respiratory disease: strategic targets for primary prevention in childhood.Thorax. 1997; 52: 1-4Crossref PubMed Scopus (80) Google Scholar Upregulation of Th1 responses is also characteristic of the immunological changes associated with successful antigen-directed immunotherapy.20Varney VA Hamid QA Gaga M et al.Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.J Clin Invest. 1993; 92: 644-651Crossref PubMed Scopus (468) Google Scholar However, although this treatment is efficacious in treating allergic disease involving the upper respiratory tract and insect venom hypersensitivity, its success in asthma is limited even if the disease is linked to exposure to a single allergen. It seems that switching an established Th2 response in the lung to one in which Th1 cytokines dominate is not easy. Defective expression of the Fas receptor or inefficient coupling of alternative pathways for apoptosis (programmed cell death) may provide avenues for research.21Castro JE Listman JA Jacobson BA et al.Fas modulation of apoptosis during negative selection of thymocytes.Immunity. 1996; 5: 617-627Summary Full Text PDF PubMed Scopus (133) Google Scholar In established asthma the situation may become more complex as in chronic atopic dermatitis in which there is evidence of a Th1 superimposed upon a Th2 response.22Wefel T Morita A Greve M et al.Allergen specificity of skin-infiltrating T cells is not restricted to a type-2 cytokine pattern in chronic skin lesions of atopic dermatitis.J Invest Dermatol. 1996; 107: 871-876Crossref PubMed Scopus (220) Google Scholar Evidence exists to suggest that in chronic and severe disease T cells removed from the airways have an enhanced capacity to generate IFN-γ and IL-4 compared with the cytokine profile of normal airway T cells.23Krug N Madden J Redington AE et al.T-cell cytokine profile evaluated at the single cell level in subjects with allergic asthma and control subjects: comparison between peripheral blood and bronchoalveolar lavage fluid.Am J Respir Cell Mol Biol. 1996; 14: 319-326Crossref PubMed Scopus (280) Google Scholar During virus-induced exacerbations of asthma it seems likely that an increase in eosinophil-mediated inflammation could in part be due to IFN-a and IFN-), production since, along with IL-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF), IFNs can also prolong eosinophil survival. In addition to causing acute exacerbations of asthma, persistence of microorganisms such as adenovirus, mycoplasma, and chlamydia may also fuel a chronic inflammatory response. In allergic asthma, dendritic cells, derived from CD34 precursors, are present in large numbers in the epithelium and submucosa of asthmatic airways and play a key part in the uptake of allergens and their subsequent processing for presentation to T cells24Semper AE Hartley JA Dendritic cells in the lung: what is their relevance to asthma?.Clin Exp Allergy. 1996; 26: 485-490Crossref PubMed Scopus (26) Google Scholar In the epithelium and submucosa, dendritic cells differentiate in the presence of stem-cell factor and GM-CSF to express CD la, MHC class II with progressive loss of their capacity to secrete IL-12. Under the influence of IL-4 and TNFα, both the high-affinity (FcεRI) and the low-affinity (FcεRII) receptors for IgE are expressed on the surface of dendritic cells which increases their antigen capturing and processing capacity.25Hartley JA Semper AE Holgate ST In vivo and in vitro expression of FcER1 in human peripheral blood (PB).Immunology. 1996; 89: 41PubMed Google Scholar After taking up antigen, dendritic cells migrate to local lymph nodes where they present selected peptides in the groove of their MHC class II molecules to the T-cell receptor. Restriction of MHC class II antigen usage for responses to specific allergens has been described for a small ragweed protein and for selected house-dust mite responses. Restriction of the T cell VP repertoire is more controversial but has been shown in animal models of allergic sensitisation.26O'Hehir RE Garman RD Greenstein JL Lamb JR The specificity and regulation of T-cell responsiveness to allergens.Ann Rev Immunol. 1991; 9: 67-95Crossref PubMed Scopus (131) Google Scholar In those who are genetically susceptible, antigen presentation to naive (Th O) CD4 T cells leads to their commitment to antigen-experienced T cells with the capacity to secrete cytokines encoded on the IL-4 gene cluster and designated Th2-like T cells.27Robinson DS Hamid Q Ying S et al.Predominant Th2-type bronchoalveolar lavage T-lymphocyte population in atopic asthma.N Engl J Med. 1992; 326: 298-304Crossref PubMed Scopus (2532) Google Scholar There is also a second pathway of T-cell differentiation in which antigens from microorganisms, in the presence of high concentrations of IL-12 from dendritic cells, leads T cells to adopt aTh1-like profile with secretion of IL-2, IFN-γ, and TNFβ (lymphotoxin). These two T-cell populations are under reciprocal cytokine control with IL-4 driving a Th2 response while IL-12 drives a Th1 response. IL-10 from Th2-like cells suppresses Th1 functions whereas the interferons inhibit Th2 responses.28Drazen JM Arm JP Austen KF Sorting out the cytokines of asthma.J Exp Med. 1996; 183: 1-5Crossref PubMed Scopus (273) Google Scholar Further direction to T-cell differentiation is provided by accessory molecules of the B7 series (B7.1, B7.2) expressed on dendritic cells interacting with CD28 on T cells.29Keane-Myers A Gause WC Linsley PS Chen S-J Wills-Karp M B7-CD28/CTLA-4 co-stimulatory pathways are required for the development of T helper cell 2-mediated allergic airway responses to inhaled antigens.J Immunol. 1997; 158: 2042-2049PubMed Google Scholar If either of these B7 molecules engages cytotoxic T-lymphocyte antigen 4 (CTLA-4) on T cells then, rather than differentiating and secreting cytokines, the cells become anergic or apoptose.21Castro JE Listman JA Jacobson BA et al.Fas modulation of apoptosis during negative selection of thymocytes.Immunity. 1996; 5: 617-627Summary Full Text PDF PubMed Scopus (133) Google Scholar, 30Palmer EM Seventer GA Human T cell differentiation is regulated by the combined action of cytokines and accessory cell-dependent co-stimulatory signals.J Immunol. 1997; 158: 1654-1662Google Scholar The relevance of the co-stimulatory molecules in driving the inflammatory response has been shown in a mouse model of asthma and in bronchial explants from asthmatic airways.31Jaffar Z Djukanović R Roberts K Holgate S Cytokine mRNA expression by lung biopsy tissue from asthmatic and normal subjects during culture.FASEB J. 1996; 10: A1054Google Scholar Through these mechanisms allergen-induced sensitisation followed by repeat exposure could lead to a chronic airway inflammatory response, but IgE-dependent mechanisms do not easily explain non-allergic (intrinsic) asthma and asthma associated with reactive occupational chemicals, such as toluidine diisocyanate. However, bronchial biopsy specimen and lavage studies have shown almost identical cytokine profiles in these asthma variant32Humbert M Durham SR Ying S et al.IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and non-atopic asthma: evidence against "intrinsic" asthma being a distinct immunopathologic entity.Am J Respir Crit Care Med. 1996; 154: 1497-1504Crossref PubMed Scopus (385) Google Scholar and, in the case of intrinsic asthma, a level of cell surface FcεRI expression inseparable from that seen in the classic allergic form of the disease.33Humbert M Grant JA Taborda-Barata L et al.High affinity IgE receptor (FcER1)-bearing cells in bronchial biopsies from atopic and non-atopic asthma.Am J Respir Crit Care Med. 1996; 153: 1931-1937Crossref PubMed Scopus (193) Google Scholar One possible explanation for these findings is a role for local (as opposed to systemic) IgE sensitisation thereby providing the necessary stimulus for disease initiation and persistence. Understandably the clinical symptoms of episodic cough, wheeze, and breathlessness led to asthma being considered as a transient disorder of airway smooth muscle. This concept fuelled the increasing use of inhaled short-acting bronchodilators, especially β2-agonists, as a principal therapy for the disease. However, while effectively relieving symptoms, these drugs do not influence the underlying mechanisms of asthma, namely airway inflammation and tissue remodelling (figure 1). The measurement of chemical mediators, including rapidly acting autacoids such as histamine and leukotrienes, proteolytic enzymes such as tryptase, and basic proteins in biological fluids obtained from patients with asthma, provide overwhelming evidence for key parts played by mast cells and eosinophils in producing airway obstruction and associated symptoms of asthma. These unique granule-containing cells originally described by Paul Ehrlich characterise the inflammatory response of asthma. Both cells originate from CD34 bone-marrow precursors. The mast cell requires the presence of stem-cell factor (SCF) secreted by epithelial and mesenchymal cells and, in the case of the mucosal mast cell, cytokines from T cells, including IL-4 and IL-6.34Yanagida M Fukamachi H Ohgami K et al.Effects of T helper 2-type cytokines, interleukin-3 (IL-3), IL-4, IL-5 and IL-6 on the survival of cultured human mast cells.Blood. 1995; 86: 3705-3714PubMed Google Scholar Eosinophils require IL-3 for initial commitment and then IL-5 and GM-CSF for maturation and cell priming.35Denburg JA Microenvironmental influences on inflammatory cell differentiation.Allergy. 1995; 50: 25-28Crossref PubMed Scopus (22) Google Scholar Mast cells, basophils, and eosinophils contain on their cell surface both high-affinity (FcεRI) and low-affinity (FcεRII) receptors for the C3 domain of IgE, the antibody responsible for providing a key activation mechanism for non-cytotoxic mediator secretion. Both B-cell switching to IgE and the expression of IgE receptors are positively regulated by IL-4 and its homologue IL-13, 36Abbas AK Murphy KM Sher A Functional diversity of helper T lymphocytes.Nature. 1996; 383: 787-793Crossref PubMed Scopus (3798) Google Scholar two cytokines which, along with IL-3, IL-5, IL-9, and GM-CSF, are encoded in a cluster on the long arm of chromosome 5 (the IL-4 gene cluster).37Wilkinson J Holgate ST Evidence for and against chromosome 5q as a region of interest in asthma and atopy.Clin Exp Allergy. 1996; 26: 861-864Crossref PubMed Scopus (7) Google Scholar Cross linkage of cell-bound IgE by relevant allergen initiates a tyrosine kinase and protein kinase C mediated exocytosis of granules containing preformed mediators and provides the necessary precursor molecules for the generation of newly formed mediators, including prostaglandins and leukotrienes. In asthma the mast-cell population, which is largely of the mucosal (MC,) rather than the connective tissue (MCT) type, is located in and close to the epithelium where it is more likely to encounter inhaled allergens.38Bradding P Walls AF Church MK Mast cells and basophils: their role in initiating and maintaining inflammatory responses.in: Holgate ST Immunopharmacology of the respiratory system. Academic Press, London1995: 53-84Crossref Google Scholar Mast-cell activation produces rapid bronchoconstriction mediated through the actions of histamine, prostaglandin D2, and leukotrienes C4, D4, and E4 (slow-reacting substance of anaphylaxis), which also increase microvascular permeability, enhance airway smooth muscle responsiveness, and initiate neutrophil and eosinophil recruitment. In addition to secreting rapidly acting mediators, IgE-dependent activation of mast cells releases a variety of preformed and newly generated cytokines including IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF, and TNFα.39Church MK Levi-Schaffer F The human mast cell.J Allergy Clin Immunol. 1997; 99: 155-160Summary Full Text Full Text PDF PubMed Scopus (302) Google Scholar These cytokines have a key role in the more prolonged inflammatory phase after allergen exposure. Recruitment by the mucosal microvasculature of neutrophils followed by eosinophils, T cells, and monocytes is initiated by the effects of histamine and leukotrienes which promote the transport of P selectin from Weibel Palade bodies to the endothelial surface (figure 2). Interaction of this adhesion molecule with sialyl-Lewisx and related lectins on the surface of leucocytes results in characteristic rolling of the leucocyte along the endothelial wall.40Springer TS Adhesion receptors of the immune system.Nature. 1990; 346: 425-434Crossref PubMed Scopus (5790) Google Scholar Within 2-3 hours of allergen exposure TNFα released from mast cells leads to the endothelial expression of further adhesion molecules, including E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-l).41Casale TB Costa JJ Galli SJ TNFα is important in human lung allergic reactions.Am J Respir Cell Mol Biol. 1996; 15: 35-44Crossref PubMed Scopus (56) Google Scholar ICAM- and VCAM-1 interact with heterodimeric integrins expressed on rolling leucocytes to produce firm adhesion, cell priming, and eventually transendothelial migration. VCAM-1 and its interaction with the integrin VLA4 (very late antigen 4) expressed on eosinophils, basophils, and T cells plays a particularly important part since it is under the dual regulation of TNFα and IL-4 (or IL-13).42Abraham WM Sielczak MW Ahmed A et al.α4-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.J Clin Invest. 1994; 93: 776-787Crossref PubMed Scopus (198) Google Scholar The migration, priming, and prolonged survival of eosinophils are important functions of IL-5 and GM-CSF, while a separate cluster of chemoattractant cytokines (chemokines), especially RANTES (regulated upon activation, normal T-cell expressed and secreted), monocyte chemotactic protein 3, eotaxin, and IL-8 are important in directing leucocyte migration through the airway wall.43Baggiolini M Dahinden CA CC chemokines in allergic inflammation.Immunol Today. 1994; 15: 127-133Summary Full Text PDF PubMed Scopus (514) Google Scholar Since these chemokines are not only generated by mast cells and T cells but also by structural components of the airway including epithelial cells, endothelial cells, smooth muscle cells, and fibroblasts, it is likely that an important interaction occurs between those factors triggering the allergic inflammatory response and those maintaining it. Unlike in antigen-sensitised animals, asthma in patients is often a lifelong disorder with a widely differing clinical picture varying over time. Like other chronic inflammatory disorders, with inadequate treatment asthma may take on an irreversible component.44Wilson JW Li X Pain MCF The lack of distensibility of asthmatic airways.Am Rev Respir Dis. 1993; 148: 806-809Crossref PubMed Scopus (122) Google Scholar Bronchial biopsy and lavage studies have provided convincing evidence that the main target for eosinophil and mast-cell attack in asthma is the bronchial epithelium which becomes fragile and loses its protective properties.45Montefort S Djukanović R Holgate ST Roche WR Ciliated cell damage in the bronchial epithelium of asthmatics and non-asthmatics.Clin Exp Allergy. 1993; 23: 185-189Crossref PubMed Scopus (48) Google Scholar In chronic asthma increased expression of the epithelial isoform of CD44 suggests that the epithelium transforms into a repair phenotype expressing a range of bioactive molecules, including cytokines, growth factors, inducible nitric oxide synthase, cyclooxygenase 2, and cytoplasmic phospholipase A2.46Lackie PM Baker JE Günthert U Holgate ST Expression of CD44 isoforms is increased in the airway epithelium of asthmatic subjects.Am J Respir Cell Mol Biol. 1997; 16: 14-22Crossref PubMed Scopus (77) Google Scholar, 47Raeburn D Webber SE Proinflammatory potential of the airway epithelium in bronchial asthma.Eur Respir J. 1994; 7: 226-233Crossref Scopus (64) Google Scholar Although it is frequently stated that the arginine-rich eosinophil-granule proteins mediate the epithelial injury in asthma, metalloendoproteases (MMPs) from the eosinophil (MMP-9), mast cell (MMP-3 and MMP-9), and from the epithelium (MMP-2 and MMP-9) are also important through their capacity to disrupt adhesion molecules that maintain the epithelial integrity.48Robinson C The airway epithelium: the origin and target of inflammatory airways disease and injury.in: Holgate ST Immunopharmacology of the respiratory system. Academic Press, London1995: 187-207Crossref Google Scholar By analogy with studies in the gastrointestinal mucosa, MMPs secreted at the leading edge of infiltrating leucocytes enhance cell penetration and simultaneously alter the airway matrix.49Pender SLF Tickle SP Docherty AJP Howie D Walter NC McDonald TT A major role for matrix metalloproteases in T cell injury in the gut.J Immunol. 1997; 158: 1582-1590PubMed Google Scholar Disruption of the epithelium with the secretion of a range of growth factors for epithelial cells, smooth muscle, and fibroblasts, together with matrix degradation, results in a tissue regenerative and remodelling response. Proteolytic destruction of the epithelial basement membrane and proliferation and stimulation of subepithelial myofibroblasts lead to the deposition of interstitial collagens types III and V.50Roche WR Beasley R Williams JH Holgate ST Subepithelial fibrosis in the bronchi of asthmatics.Lancet. 1989; i: 520-523Summary Scopus (952) Google Scholar Proliferation of airway smooth muscle and the microvascular tissue leads to a structurally altered airway that over time contributes to disease chronicity.51Holgate ST Djukanović R Howarth PH Montefort S Roche W The T-cell and the airways fibrotic response in asthma.Chest. 1993; 103: 125S-128SCrossref PubMed Google Scholar Chronicity is further enhanced by the gradual acquisition of allergen-independent T-cell expansion involving not only CD4 but also CD8 cells that, in the presence of high concentrations of IL-4, also secrete a full range of cytokines encoded in the IL-4 gene cluster.52Stanciu LA, Shute J, Promwong C, Holgate ST, Djukanović R. Increased levels of IL-4 in CD8+T cells in atopic asthma. J Allergy Clin Immunol (in press).Google Scholar A further consequence of damage to the bronchial epithelium is the upregulation of viral receptors, such as ICAM-1, which render the airway more susceptible to invasion by respiratory viruses especially those that cause the common cold.53Tomassini JE Graham D DeWitt CM Lineberger DW Rodkey JA Colonno RJ cDNA cloning reveals that the major group rhinovirus receptor on HeLa cells is intercellular adhesion molecule 1.in: 2nd ed. Proc Natl Acad Sci. 86. 1989: 4907-4911Google Scholar More than 80% of asthma exacerbations in children and in adults can be traced to respiratory viruses54Johnston SL Pattemore PK Sanderson G et al.Community study of role of viral infections in exacerbations of asthma in school children in the community.BMJ. 1995; 310: 1225-1229Crossref PubMed Scopus (1622) Google Scholar whose action on the mucosal epithelium and T-cell population is to augment cytokine release although the precise mechanisms involved have yet to be elucidated.55Fraenkel DJ Bardin PG Sanderson G Lampe F Johnston SL Holgate ST Lower airway inflammatory response during rhinovirus colds in normal and asthmatic subjects.Am J Respir Crit Care Med. 1995; 151: 879-886Crossref PubMed Scopus (366) Google Scholar Recognising that most asthma has its origin in early life, there are unique opportunities for primary prevention. Although many of these are untested, possible fruitful approaches in high-risk families are allergen avoidance (including in pregnancy), augmentation of the Th1 response (eg, by microbial vaccination at a critical time during the period when the mucosal immune response becomes deviated to a Th2 profile by allergen), and pharmacological intervention with agents that might inhibit B-cell isotype switching to IgE (eg, sodium cromoglycate, nedocromil sodium), reduce dendritic cell and T-cell signalling (inhaled corticosteroids), or reduce the expression of cell adhesion molecules such as ICAM-(some antihistamines). Once established, mild inflammatory responses can be downregulated by cromone-like drugs which, through blockage of volume-regulated chloride channels, are thought to inhibit mast cell, eosinophil, afferent neural, and epithelial cell functions. More severe inflammation responds to topical corticosteroids which inhibit cytokine generation and reduce the expression of cytokine-inducible genes such as those for endothelin, cyclooxygenase 2, cytoplasmic phospholipase A2 (cPLA2), and inducible nitric oxide synthase. In a retrospective review of 175 children aged 0.2-16.8 years treatment with either sodium cromoglycate or inhaled corticosteroids, but not as-needed β-bronchodilators, over about 8 years has been shown to impove the long-term prognosis of asthma.56König P Shaffer J The effect of drug therapy on long-term outcome of childhood asthma: a possible preview of the international guidelines.Allergy Clin Immunol. 1996; 98: 1103-1111Summary Full Text Full Text PDF Scopus (89) Google Scholar Whether one chooses a non-steroid or a steroid as an anti-inflammatory agent, the key to successful asthma management depends upon early and effective treatment before airway remodelling has time to get a hold and permanently alter airway function. Thus, knowledge of disease pathogenesis has a substantial part to play in informing diagnostic and therapeutic strategies for asthma and in ensuring that the further development of asthma guidelines is evidence-based. The variable and complex clinical presentations of asthma are the consequences of an interplay between T-lymphocyte mediated airway inflammation, tissue destruction, and remodelling. Recognising that most asthma begins early in life, an accurate diagnosis and appropriate environment and pharmacological interventions are the keys to effective disease management and underpin national and international guidelines. A clearer understanding of the cellular and molecular mechanisms involved in disease induction and progression offers considerable promise for the discovery of treatments that will modify the disease outcome rather than simply suppressing the inflammatory processes.
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