Pulmão profundo – Reacção celular ao VIH

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array:2 [ "nombre" => "António" "apellidos" => "Caiado" ] 3 => array:2 [ "nombre" => "Susana" "apellidos" => "Ferreira" ] 4 => array:2 [ "nombre" => "Paula" "apellidos" => "Ferreira" ] 5 => array:2 [ "nombre" => "Lino" "apellidos" => "Santos" ] 6 => array:2 [ "nombre" => "Manuel" "apellidos" => "Gonçalves" ] 7 => array:2 [ "nombre" => "Teresa" "apellidos" => "Shiang" ] ] ] ] ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0873215915303469?idApp=UINPBA00004E" "url" => "/08732159/0000001300000002/v1_201509071322/S0873215915303469/v1_201509071322/pt/main.assets" ] "pt" => array:15 [ "idiomaDefecto" => true "cabecera" => "Prémio Thomé Villar / Boehringer Ingelheim 2005 (Secção A) / Thomé Villar / Boehringer Ingelheim Award 2005 (Section A)" "titulo" => "Pulmão profundo – Reacção celular ao VIH" "tieneTextoCompleto" => 0 "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "175" "paginaFinal" => "212" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Maria Alcide Tavares Marques, Vera Alves, Victor Duque, M. Filomena Botelho" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Maria Alcide Tavares" "apellidos" => "Marques" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "1" "identificador" => "af0005" ] ] ] 1 => array:3 [ "nombre" => "Vera" "apellidos" => "Alves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "2" "identificador" => "af0010" ] ] ] 2 => array:3 [ "nombre" => "Victor" "apellidos" => "Duque" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "3" "identificador" => "af0015" ] ] ] 3 => array:3 [ "nombre" => "M. Filomena" "apellidos" => "Botelho" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "4" "identificador" => "af0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Departamento de Ciências Pneumológicas e Alergológicas dos Hospitais da Universidade de Coimbra (Director: Prof. Doutor M Fontes Baganha)" "etiqueta" => "1" "identificador" => "af0005" ] 1 => array:3 [ "entidad" => "Instituto de Imunologia da Faculdade de Medicina de Coimbra (Director: Prof. Doutor Santos Rosa)" "etiqueta" => "2" "identificador" => "af0010" ] 2 => array:3 [ "entidad" => "Departamento de Doenças Infecciosas dos Hospitais da Universidade de Coimbra (Director: Prof. Doutor Meliço Silvestre)" "etiqueta" => "3" "identificador" => "af0015" ] 3 => array:3 [ "entidad" => "Instituto de Biofísica/Biomatemática da Faculdade de Medicina de Coimbra(Directora: Prof.ª Doutora M Filomena Botelho)" "etiqueta" => "4" "identificador" => "af0020" ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Deep lung – Cellular reaction to HIV" ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2006-12-10" "fechaAceptado" => "2006-12-19" "PalabrasClave" => array:2 [ "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec567847" "palabras" => array:4 [ 0 => "Lavagem broncoalveolar" 1 => "SIDA" 2 => "celularidade" 3 => "receptores CCR5 e CXCR4" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key-words" "identificador" => "xpalclavsec567846" "palabras" => array:4 [ 0 => "Bronchoalveolar lavage" 1 => "AIDS" 2 => "cellularity" 3 => "CCR5 and CXCR4 receptors" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "A evolução da infecção VIH é caracterizada por uma grande variabilidade individual. Na verdade, como em outros processos da mesma natureza, depende largamente das complexas inter-relacções que num dado momento se esta-belecem entre o hospedeiro e o agente agressor. Contudo, nesta infecção, essa correlação assume um papel determinante. Desde o início da pandemia que o pulmão se assumiu como alvo preferencial de complicações, quer de origem infecciosa quer de outras etiologias. A esta inevitabilidade biológica diríamos não serem de facto estranhas as carac-terísticas anatomo-funcionais do órgão, enquanto interface privilegiada entre o meio interno e o ambiente exterior, aliadas a particularidades de ordem imunológica que o tor-nam, sob muitos aspectos, um órgão único.Cedo se constatou que esta infecção se acompanhava de uma disfunção imunológica progressiva que culminava na completa exaustão deste sistema nas fases terminais da doença. Desde o reconhecimento da SIDA até à presente data foram sendo adquiridos enormes conhecimentos não só em relação ao vírus, como aos seus mecanis mos patogénicos, no entanto subsistem ainda numerosas questões para as quais o estado da arte ainda não dispõe de respostas. Nessas incluíriamos os efeitos do VIH na dinâmica celular do pulmão. Vários estudos efectuados, nos quais tivemos oportunidade de participar, demonstraram a apresença de uma alveolite linfocitária durante a fase assintomática da infecção. Desde essa altura têm-se vindo a adquirir novos conhecimentos relativos aos mecanismos imunológicos e bioquímicos subja-centes à entrada do VIH nas células, às células-alvo, ao microambiente citocínico, assim como de outros media-dores celulares envolvidos. Neste contexto, a descoberta de que receptores específicos de quimiocinas actuavam como co-receptores para o VIH abriu definitivamente um novo capítulo na investigação dirigida aos mecanismos responsáveis pelo tropismo viral e infecção celular. Neste âmbito, vários autores têm salientado a importância, para além da molécula CD4, dos receptores quimiocínicos CCR5 e CXCR4 na ligação e, posterior-mente, na entrada do vírus nas células, reconhecendo-se em relação ao primeiro uma importância fundamental na transmissão da infecção, enquanto que o CXCR4 parece ser utilizado por estirpes virais que emergem tardia-mente no decurso da doença, quer isoladamente, quer em associação com o CCR5.Objectivo: O nosso estudo dirigiu-se fundamentalmente à avaliação da dinâmica celular do pulmão profundo em doentes com SIDA, abarcando a determinação das cargas virais no líquido de lavagem broncoalveolar (LLBA), a celularidade envolvida nos mecanismos de defesa desse território e tropismo viral, através dos receptores quimiocínicos CCR5 e CXCR4.Material: Estudámos 14 doentes portadores de SIDA, com uma média de idades de 39±14,3 anos (9 homens e 5 mulheres) todos infectados pelo VIH1, heterossexuais, dos quais 6 eram fumadores e 8 não fumadores, e sem antecedentes de toxicodependência. Estes doentes foram referenciados pelo Deparamento de Doenças Infecciosas dos Hospitais da Universidade de Coimbra para a realiza-ção de broncofibroscopia e lavagem broncoalveolar (LBA), por suspeita clínica de infecção pulmonar oportunista. Posteriormente, este conjunto de doentes seria dividido e analisado em dois grupos: Grupo I, designado por diag-nóstico recente e Grupo II, englobando os de diagnóstico não recente. De facto, embora todos estes doentes fossem portadores de SIDA, a Amostra Clínica era constituída por indivíduos com infecções oportunistas de diagnóstico recente, nos quais ainda não tinha sido instituída terapêutica anti-retroviral, primeiro grupo, enquanto o segundo grupo incluía doentes com doença mais prolongada, com vários episódios infecciosos oportunistas e tratamento anti-retroviral, para além de outros esquemas terapêuticos.Métodos: Todos os doentes após, consentimento informado, foram submetidos a exame broncoendoscó-pico e LBA, após anestesia local da orofaringe e cordas vocais com lidocaína a 2%, sob monitorização cárdio-respiratória. O LBA foi efectuado com base nas alterações evidenciadas pela telerradiografia do tórax: lobo médio nas lesões difusas, ou outro brônquio segmentar correspondente a alterações radiológicas localizadas A determinação das cargas virais no líquido de lavagem broncoalveolar (LLBA), em 9 doentes, foi efectuada pela quantificação do ARN-VIH1, através de PCR-RT, nas primeiras 4horas após a colheita (sendo cada amostra centrifugada), procedendose posteriomente nas aliquo-tas do sobrenadante à congelação a menos 80º C, até à extracção e amplificação dos ácidos nucleicos. Realizou-se igualmente, na totalidade da amostra, a determinação das viremias plasmáticas (14 doentes), a partir de amostras de sangue colhido em EDTA, com processa-mento ulterior (separação do plasma e congelamento a menos 80ºC). A extração e amplificação dos ácidos nucleicos foi efectuada por um método automatizado Cobas Ampliprep/Cobas Amplicor HIV1 Monitor TM Test, version 1.5 Roche Diagnostic Systems. Este método permite a obtenção duma sequência de 155 nucleótidos situada numa região altamente conservada do gene gag. Os resultados foram observados numa escala numérica com uma variação dinâmica situada entre as 50 e 750 000 cópias de ARN VIH1/cm3, procedendo-se posterior-mente à sua conversão logarítmica.No LLBA (10 doentes) e no sangue (13 doentes) foi efectuado um estudo imunológico, dirigido à quantificação das populações e subpopulações linfocitárias: CD3, CD4, CD8, CD19, CD56 e CD56CD8, assim como dos receptores: CD3CCR5, CD4CCR5, CD8CCR5, CCR5Mø, CXCR4, CD3CXCR4, CXCR4CD14 e da molécula de co-esti-mulação CD28, CD3CD28, CD4CD28, CD8CD28 através de anticorpos monoclonais – CD8FITC, CD19FITC, CD3PE, CD56PE, CD4PECY5-Lymphogram Cytognos; CCR5PE, CXCRFITC-R & D Systems; CD8Cy5 e CD3Cy5 - DaKo, CD4PE, CD14PE, CD28FITC – Immunotech; CD4FITC-CLB, CD8Percp – Beckton Dickinson e CD3 APC – Beckton Dickinson, por cito-metria de fluxo (Facs Calibur-Beckton-Dickinson) a 3 ou 4 fluorescências – FL1-FITC, FL2-PE, FL3-PECY, FL4-APC. Na análise estatística dos resultados foram utilizados os testes t -Student e de correlação linear.Resultados: Salientamos os seguintes: presença do vírus no LLBA (2,95 log±3,08 log), embora em quantidades inferiores às detectadas no sangue(5,89 log±5,90)e grande varibilidade das cargas virais, tanto no sangue como no LLBA, independente do período de tempo entre o diagnóstico e a realização do exame; as populações e subpopulações linfocitárias no sangue (Quadro V), em 13 doentes, mostraram uma queda acentuada, tanto dos linfócitos totais como das suas populações e subpopulações, que atingia maior expressão nas células T-CD4. Apenas em 2 casos (doentes n.os 12 e 13) esta subpopulação era superior a 250 células/mm3 e em 42,9% era inferior a 50 células/mm3. A população CD19 encontrava-se igualmente em níveis inferiores ao normal com uma distribuição individual se-melhante à da subpopulação CD4. Na maior parte dos casos, a diminuição dos CD8 acompanhava a redução dos CD4 e CD19(doentes n.os 7 e 8); na LLBA (Quadro VI), o estudo das populações e subpopulações linfocitárias (10 doentes) revelou uma distribuição percentual seme-lhante à que foi observada no sangue(Quadro VII) em relação às células CD3, CD19, CD4 e CD8, embora no LLBA a percentagem de linfócitos-T fosse superior neste meio em relação ao sangue(94,5±5 /84,1±10,4), ao contrário do que se observou nos linfócitos-B (2,2±3 /10,4±9,6). Também no LLBA se verificou uma percentagem mais elevada de linfócitos-T CD8 do que no sangue (77,7±17,6 /67,6±4,2), o que não se observou em relação às células T-CD4 (8,1±9,5 LLBA vs.10,4±9,6 no sangue); a actividade natural killer (NK) expressa pelas células T CD56 apresentava importantes variações individuais em ambos os meios, mas com valores mais elevados no sangue do que no LLBA (9,1±8/2,9±1,9); quanto à actividade citotóxica avaliada através das células CD56CD8, era similar no LLBA e no sangue (2,2±2/1,7±1,2), parecendo, contudo, que a distribuição individual era mais homogénea no primeiros destes meios (Quadros VI e VII); as céulas duplamente negativas (DN) apresentavam-se com valores ligeiramente mais elevados no LLBA (7,6±4,5 vs 5,6±± 5,3). Curiosamente, neste meio observa-se uma percentagem elevada das células menos diferenciadas (13±13,6) (Quadro VI). A análise dos receptores celulares CCR5 e CXCR4 mostrou, em termos globais e médios, diferentes comportamentos entre si e em relação aos meios biológicos (Quadros VI e VII). Assim, o CCR5 CD3 era mais elevado no sangue (10,9±13,2) do que no LLBA (8,4±± 3,5); no entanto, o CCR5 CD4 e a CCR5 CD8 en-contravam-se em maior percentagem no LLBA do que no sangue (2±2,3 e 4,9±3,7/0,9±0,7 e 4,1±4,0 respec-tivamente). No que diz respeito aos valores deste receptor na linha monocítica-macrofágica ele apresentava-se muito mais elevados no LLBA (77,8±41 no LLBA vs. 18,7±± 15 no sangue). Pelo contrário, o CXCR4 total era mais elevado no LLBA 31±19,9) do que no sangue (16,4±± 8,1); esta tendência manisfestava-se igualmente em relação aos linfócitos-T (26,6±19,8 vs. 10,7±7,6) e à linha monocítica-macrofágica, aliás, de uma forma exuberante (84,5±30,2 / 4,8±4,6). A actividade co-estimulatória CD28 mostrou-se superior no sangue (22,8±16,2)em comparação com o LLBA(15,9±10,1)para as células T totais, CD4 e CD8(22,5 16,7; 7,8±8,3; 13,3±8,3 / / 16,5±10,5; 2,9±2,8; 10,8±8,0, respectivamente).Conclusões:<ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="o0105">1.A infecção VIH é reponsável por extensas e diversificadas alterações nos mecanismos de defesa do pulmão profundo.</li><li class="elsevierStyleListItem" id="o0010">2.A complexa interacçãoo entre o hospedeiro e o agente agressor, bem como a resposta imunológica, particularmente a natural killer e citotóxica, apoptose e doenças oportunistas, ou outras, podem dificultar a obtenção de amostras médicas homogéneas. Para além disso, considerações de ordem ética restringem, natu-ralmente, a abordagem destes doentes com finalidades exclusivamente científicas.</li><li class="elsevierStyleListItem" id="o0015">3.Os resultados obtidos apontam tendencialmente para uma resposta pulmonar compartimentada à agressão VIH, com base na dinâmica celular envolvida e no perfil dos receptores encontrado nos líquidos biológicos estudados. Neste contexto, esta compartimentação parece estar particularmente na dependência da actividade dos macrófagos alveolares que constituem, desde o início, o eixo fundamental destes processos, representando o últi-mo mecanismo celular de defesa deste território, quando os outros estão já profundamente alterados.</li><li class="elsevierStyleListItem" id="o0025">4.O estudo da dinâmica dos receptores quimiocínicos pode vir a ter importantes implicações terapêu-ticas. De facto, foi já demonstrado que o bloqueio do receptor CCR5 não foi acompanhado por um aumento da expressão do receptor CXCR4. Neste estudo tivemos oportunidade de verificar que o CXCR4 se manteve elevado nas células monocíticas-macrofágicas durante a doença, aumentando a sua expressão nos linfócitos T nos doentes do Grupo II, ao contrário do comportamento do CCR5 no LLBA, que dimi-nuía significativamente. No sangue, porém, a expressão do CCR5 aumentava.</li><li class="elsevierStyleListItem" id="o0035">5.A elevada co-existência de infecções oportunistas (71,4%) leva-nos a colocar a hipótese de que a modulação induzida pelos germes possa contribuir para a elevada expressão do CXCR4.</li><li class="elsevierStyleListItem" id="o0045">6.Finalmente, esta tão marcada variabilidade individual tem indiscutivelmente implicações clínicas. Em termos gerais, podemos dizer que, para uma mais correcta abordagem terapêutica, cada doente deve ser prévia e individualmente analisado neste contexto.</li></ul>Rev Port Pneumol 2007; XIII (2): 175-212" ] "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The course of HIV infection is accompanied by a wide individual variability. The complex and large in-terplay between host and viral factors is crucial in the disease’s evolution. The lung has been recognised from the beginning of the disease as one of the main targets of infectious and non-infectious complications of AIDS. In this setting both anatomic and immunologic particularities of this organ play an important role.The hallmark of HIV is progressive immune dys-function. Despite the intensive research into the pathogenesis, several questions remain to be answered on the dynamic effects of HIV on pulmonary cells. Previous studies in which we have participated sho-wed the early presence of lymphocytic alveolitis from the asymptomatic phase of infection. Since then, many collected data has brought new insights into the immune and biochemical mechanisms involving HIV cell entry, as well as target cells, cytokines and other cellular mediators.In this context, the discovery that specific chemokine receptors could act as co-receptors for HIV, allowed a better understanding of the mechanisms underlying viral cellular entry and tropism. On this issue several authors have reported that in addition to the CD4 molecule, most strains of HIV use the chemokine receptor CCR5 for viral attachment and entry into the host cells. This receptor seems to be very important in disease transmission, whereas CXCR4 receptor tends to be used by the viral strains that emerge later in the disease in addition to or instead of the CCR5.Aims: To evaluate the pulmonary cellular dynamics in AIDS patients regarding the viral load in bronchoalveolar lavage fluid (LLBA), as well as cellularity and tropism through CCR5 and CXCR4 receptors.Material: 14 AIDS patients were enrolled in this study, with a mean age of 39±14.3years (9 males and 5 females) all HIV1, heterosexuals, 6 smokers and 8 non-smokers, none of them drug addicts. These patients were referred to bronchoscopy with BAL, for clinical suspicion of opportunistic lung infections. These patients were later divided into two groups: Group I (recent diagnosis) and Group II (non-recent diagnosis). While all patients had AIDS, group I had also recent diagnosis of oportunistic infections and had not received yet anti-retroviral therapy whilst group II had a long-term disease evolution with several opportunistic episodes and anti-retroviral therapeutic.Methods: BAL was performed both in the middle bronchus in diffuse or in other segmentar bronchus, depending on radiographic abnormalities. Plasma viral load was performed through PCR-RT in blood samples with EDTA, centrifuged and frozen (-80º Cel-sius) in the first 4 hours after being collected. The viral load in BALf was quantified in 9 patients using the automatized Cobas Ampliprep/Cobas Amplicor HIV1 Monitor TM Test, version 1.5 Roche Diagnostic Systems. The results were expressed in a numeric scale, with a dynamic variation of 50-750.000 copies of RNA HIV1/cm3 and later converted into a logarithmic scale.In 10 patients an immunological study was carried out in BALf and blood to quantify the lymphocyte populations and subsets (CD3, CD4, CD8, CD19, CD56 and CD56CD8) as well as the receptors CD3CCR5, CD4CCR5, CD8CCR5, CCR5Mø, CXCR4, CD3CXCR4, CXCR4CD14 and co-stimulatory molecule CD28, CD3CD28, CD4CD28, CD8CD28 through monoclonal antibodies – CD8FITC, CD19FITC, CD3PE, CD56PE, CD4PECY5-Lymphogram Cytognos; CCR5PE, CXCRFITC-R & D Systems; CD8Cy5 and CD3Cy5-DaKo, CD4PE, CD14PE, CD28FITC-Immunotech; CD4FITC-CLB, CD8Percp- Beckton Dickinson and CD3 APC – Beckton Dickinson, by flow cytometry (Facs Calibur-Be-ckton-Dickinson) with 3 or 4 fluorescences – FL1-FITC, FL2-PE, FL3-PECY, FL4-APC. In the statistical analysis, we used the Student t-test, and linear correlation.Results: Presence of HIV1 in BALf (2.95 log±3.08 log), in small levels compared with plasma viral loads (5.89 log ±5.90 log) (Table IV).There was great variability of viral loads in BALf as there was in blood independent of the time elapsed between diagnosis and the exam.As for the lymphocytic populations and subsets in blood (Table V) determined in 13 patients, there was a significant fall of total lymphocytes as well as of their subsets, although more marked in CD4 cells; 42.9% had CD4 levels < 50 cels/mm3 and only 2 patients (nº 12, 13) had CD4> 250 cels/mm3. The CD19 was reduced with an individual distribution similar to the CD4 subset. In most cases, the fall of CD8 accompanied the decrease of CD4 and CD19 (patients-nº 7 and 8). The lymphocyte populations and subsets in BALf (10 patients) (Table VI) showed a percentual distribution similar to that observed in blood (Table VII) for CD3, CD19, CD4 and CD8 lymphocytes, although the percentage of T cells was higher than in blood (94.5±5 /84.1±10.4) as opposed to B cells (2.2±3 /10.4±9.6). In BALf CD8T cells were higher than in blood (77.7±17.6 /67.6±4.2), which was not observed for the CD4 lymphocytes (8.1±9.5 BALf vs.10.4±9.6 in blood). The natural killer activity expressed by CD56T cells had important indivi-dual variations in both biological fluids: higher levels in blood than in BALf (9.1±8 /2.9±1.9). The cytotoxic activity of CD56CD8 was similar in blood and in BALf (2.2±2 / 1.7±1.2) while the individual distribution seemed more homogeneous in BALf (Table VI) than in blood (Table VII). The double-negative (DN) cells had slightly higher values in BALf (7.6±4.5 vs 5.6±5.3). Curiously, in BALf we observed a higher percentage of less differenciated cells (13±13.6) (Table VI). The analysis of the receptors CCR5 and CXCR4 showed in general terms different behaviour concerning the two biological means (Tables VI and VII). Thus, the CCR5 CD3 was hi-gher in blood (10.9±13.2) than in BALf (8.4±± 3.5) while the CCR5 CD4 and CCR5 CD8 had an increased expression in BALf in relation to blood (2±2.3 and 4.9±3.7 / 0.9±0.7 and 4.1±4.0 respectively). Concerning the expression of this receptor on monocyte macrophage lineage a marked higher value was attained in BALft (77.8±± 41 in BALf vs. 18.7±15 in blood). On the contrary the total expression of CXCR4 was higher in BALf (31±19.9) than in blood (16.4±± 8.1). This tendency extended equally to the T lymphocytes (26.6±19.8 vs. 10.7±7.6) and also to the monocyte-macrophage lineage in an exuberant manner (84.5±30.2 / 4.8±4.6). The co-stimulatory activity of CD28 showed higher values in blood (22.8±16.2) than in BALf (15.9±± 10.1) for total T cells, CD4 and CD8 lymphocytes 22.5±16.7; 7.8±8.3; 13.3±8.3 / 16.5±± 10.5; 2.9±2.8; 10.8±8.0 respectively).Conclusions:<ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="o0055">1.HIV infection is responsible for important and extensive abnormalities in lung host defences.</li><li class="elsevierStyleListItem" id="o0065">2.The complex interaction between host and aggressor as well as the immune response particularly represented by natural killer and cytotoxic activities, apoptosis, and opportunistic diseases or others, therapeutics and other factors may contibute to the difficulty in obtaining homogenous medical samples within research. There are also ethical issues that restrict a purely scientific approach to these patients.</li><li class="elsevierStyleListItem" id="o0075">3.These results point to a pulmonary response to HIV in a compartmentalised fashion according to the dynamic cellular elements involved and receptors in which the latter had distinct profiles related to the biological fluids. In this context, the lung compartimental response is particularly dependent on alveolar macrophages activity which is from the beginning the cornerstone of this process and is the last cellular defense mechanism in this territory when all others are profoundly affected.</li><li class="elsevierStyleListItem" id="o0085">4.The dynamics of chemokines receptors may be very important in therapeutic approach as the blockage of the CCR5 receptor does not seem to trigger an increased expression of CXCR4 strains. In fact, we found that CXCR4 remained high in monocyte-macrophage cells throughout infection and its expression was increased in T-lymphocytes in Group II patients as opposed to CCR5 behavior in BALf which significantly decreases. However, in blood, CCR5 expression increased, unlike CXCR4.</li><li class="elsevierStyleListItem" id="o0095">5.Due to high co-existing opportunistic infections (71.4%) we cannot ignore the hypothesis that this increased expression of CXCR4 was a result of the modulation induced by opportunistic agents.</li><li class="elsevierStyleListItem" id="o0100">6.Finally, this striking individual variability undoubtly has clinical implications. 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Prémio Thomé Villar / Boehringer Ingelheim 2005 (Secção A) / Thomé Villar / Boehringer Ingelheim Award 2005 (Section A)

Pulmão profundo – Reacção celular ao VIH

Deep lung – Cellular reaction to HIV

Maria Alcide Tavares Marques1, Vera Alves2, Victor Duque3, M. Filomena Botelho4

1 Departamento de Ciências Pneumológicas e Alergológicas dos Hospitais da Universidade de Coimbra (Director: Prof. Doutor M Fontes Baganha)

2 Instituto de Imunologia da Faculdade de Medicina de Coimbra (Director: Prof. Doutor Santos Rosa)

3 Departamento de Doenças Infecciosas dos Hospitais da Universidade de Coimbra (Director: Prof. Doutor Meliço Silvestre)

4 Instituto de Biofísica/Biomatemática da Faculdade de Medicina de Coimbra(Directora: Prof.ª Doutora M Filomena Botelho)

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        "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">A evolu&#231;&#227;o da infec&#231;&#227;o VIH &#233; caracterizada por uma grande variabilidade individual&#46; Na verdade&#44; como em outros processos da mesma natureza&#44; depende largamente das complexas inter-relac&#231;&#245;es que num dado momento se esta-belecem entre o hospedeiro e o agente agressor&#46; Contudo&#44; nesta infec&#231;&#227;o&#44; essa correla&#231;&#227;o assume um papel determinante&#46; Desde o in&#237;cio da pandemia que o pulm&#227;o se assumiu como alvo preferencial de complica&#231;&#245;es&#44; quer de origem infecciosa quer de outras etiologias&#46; A esta inevitabilidade biol&#243;gica dir&#237;amos n&#227;o serem de facto estranhas as carac-ter&#237;sticas anatomo-funcionais do &#243;rg&#227;o&#44; enquanto interface privilegiada entre o meio interno e o ambiente exterior&#44; aliadas a particularidades de ordem imunol&#243;gica que o tor-nam&#44; sob muitos aspectos&#44; um &#243;rg&#227;o &#250;nico&#46;</p><p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Cedo se constatou que esta infec&#231;&#227;o se acompanhava de uma disfun&#231;&#227;o imunol&#243;gica progressiva que culminava na completa exaust&#227;o deste sistema nas fases terminais da doen&#231;a&#46; Desde o reconhecimento da SIDA at&#233; &#224; presente data foram sendo adquiridos enormes conhecimentos n&#227;o s&#243; em rela&#231;&#227;o ao v&#237;rus&#44; como aos seus mecanis mos patog&#233;nicos&#44; no entanto subsistem ainda numerosas quest&#245;es para as quais o estado da arte ainda n&#227;o disp&#245;e de respostas&#46; Nessas inclu&#237;riamos os efeitos do VIH na din&#226;mica celular do pulm&#227;o&#46; V&#225;rios estudos efectuados&#44; nos quais tivemos oportunidade de participar&#44; demonstraram a apresen&#231;a de uma alveolite linfocit&#225;ria durante a fase assintom&#225;tica da infec&#231;&#227;o&#46; Desde essa altura t&#234;m-se vindo a adquirir novos conhecimentos relativos aos mecanismos imunol&#243;gicos e bioqu&#237;micos subja-centes &#224; entrada do VIH nas c&#233;lulas&#44; &#224;s c&#233;lulas-alvo&#44; ao microambiente citoc&#237;nico&#44; assim como de outros media-dores celulares envolvidos&#46; Neste contexto&#44; a descoberta de que receptores espec&#237;ficos de quimiocinas actuavam como co-receptores para o VIH abriu definitivamente um novo cap&#237;tulo na investiga&#231;&#227;o dirigida aos mecanismos respons&#225;veis pelo tropismo viral e infec&#231;&#227;o celular&#46; Neste &#226;mbito&#44; v&#225;rios autores t&#234;m salientado a import&#226;ncia&#44; para al&#233;m da mol&#233;cula CD4&#44; dos receptores quimioc&#237;nicos CCR5 e CXCR4 na liga&#231;&#227;o e&#44; posterior-mente&#44; na entrada do v&#237;rus nas c&#233;lulas&#44; reconhecendo-se em rela&#231;&#227;o ao primeiro uma import&#226;ncia fundamental na transmiss&#227;o da infec&#231;&#227;o&#44; enquanto que o CXCR4 parece ser utilizado por estirpes virais que emergem tardia-mente no decurso da doen&#231;a&#44; quer isoladamente&#44; quer em associa&#231;&#227;o com o CCR5&#46;</p><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Objectivo&#58;</span> O nosso estudo dirigiu-se fundamentalmente &#224; avalia&#231;&#227;o da din&#226;mica celular do pulm&#227;o profundo em doentes com SIDA&#44; abarcando a determina&#231;&#227;o das cargas virais no l&#237;quido de lavagem broncoalveolar &#40;LLBA&#41;&#44; a celularidade envolvida nos mecanismos de defesa desse territ&#243;rio e tropismo viral&#44; atrav&#233;s dos receptores quimioc&#237;nicos CCR5 e CXCR4&#46;</p><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material&#58;</span> Estud&#225;mos 14 doentes portadores de SIDA&#44; com uma m&#233;dia de idades de 39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;3 anos &#40;9 homens e 5 mulheres&#41; todos infectados pelo VIH1&#44; heterossexuais&#44; dos quais 6 eram fumadores e 8 n&#227;o fumadores&#44; e sem antecedentes de toxicodepend&#234;ncia&#46; Estes doentes foram referenciados pelo Deparamento de Doen&#231;as Infecciosas dos Hospitais da Universidade de Coimbra para a realiza-&#231;&#227;o de broncofibroscopia e lavagem broncoalveolar &#40;LBA&#41;&#44; por suspeita cl&#237;nica de infec&#231;&#227;o pulmonar oportunista&#46; Posteriormente&#44; este conjunto de doentes seria dividido e analisado em dois grupos&#58; Grupo I&#44; designado por diag-n&#243;stico recente e Grupo II&#44; englobando os de diagn&#243;stico n&#227;o recente&#46; De facto&#44; embora todos estes doentes fossem portadores de SIDA&#44; a Amostra Cl&#237;nica era constitu&#237;da por indiv&#237;duos com infec&#231;&#245;es oportunistas de diagn&#243;stico recente&#44; nos quais ainda n&#227;o tinha sido institu&#237;da terap&#234;utica anti-retroviral&#44; primeiro grupo&#44; enquanto o segundo grupo inclu&#237;a doentes com doen&#231;a mais prolongada&#44; com v&#225;rios epis&#243;dios infecciosos oportunistas e tratamento anti-retroviral&#44; para al&#233;m de outros esquemas terap&#234;uticos&#46;</p><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">M&#233;todos&#58;</span> Todos os doentes ap&#243;s&#44; consentimento informado&#44; foram submetidos a exame broncoendosc&#243;-pico e LBA&#44; ap&#243;s anestesia local da orofaringe e cordas vocais com lidoca&#237;na a 2&#37;&#44; sob monitoriza&#231;&#227;o c&#225;rdio-respirat&#243;ria&#46; O LBA foi efectuado com base nas altera&#231;&#245;es evidenciadas pela telerradiografia do t&#243;rax&#58; lobo m&#233;dio nas les&#245;es difusas&#44; ou outro br&#244;nquio segmentar correspondente a altera&#231;&#245;es radiol&#243;gicas localizadas A determina&#231;&#227;o das cargas virais no l&#237;quido de lavagem broncoalveolar &#40;LLBA&#41;&#44; em 9 doentes&#44; foi efectuada pela quantifica&#231;&#227;o do ARN-VIH1&#44; atrav&#233;s de PCR-RT&#44; nas primeiras 4horas ap&#243;s a colheita &#40;sendo cada amostra centrifugada&#41;&#44; procedendose posteriomente nas aliquo-tas do sobrenadante &#224; congela&#231;&#227;o a menos 80<span class="elsevierStyleHsp" style=""></span>&#186; C&#44; at&#233; &#224; extrac&#231;&#227;o e amplifica&#231;&#227;o dos &#225;cidos nucleicos&#46; Realizou-se igualmente&#44; na totalidade da amostra&#44; a determina&#231;&#227;o das viremias plasm&#225;ticas &#40;14 doentes&#41;&#44; a partir de amostras de sangue colhido em EDTA&#44; com processa-mento ulterior &#40;separa&#231;&#227;o do plasma e congelamento a menos 80<span class="elsevierStyleHsp" style=""></span>&#186;C&#41;&#46; A extra&#231;&#227;o e amplifica&#231;&#227;o dos &#225;cidos nucleicos foi efectuada por um m&#233;todo automatizado <span class="elsevierStyleItalic">Cobas Ampliprep&#47;Cobas Amplicor HIV1 Monitor TM Test&#44; version 1&#46;5 Roche Diagnostic Systems</span>&#46; Este m&#233;todo permite a obten&#231;&#227;o duma sequ&#234;ncia de 155 nucle&#243;tidos situada numa regi&#227;o altamente conservada do gene <span class="elsevierStyleItalic">gag</span>&#46; Os resultados foram observados numa escala num&#233;rica com uma varia&#231;&#227;o din&#226;mica situada entre as 50 e 750 000 c&#243;pias de ARN VIH1&#47;cm<span class="elsevierStyleSup">3</span>&#44; procedendo-se posterior-mente &#224; sua convers&#227;o logar&#237;tmica&#46;</p><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">No LLBA &#40;10 doentes&#41; e no sangue &#40;13 doentes&#41; foi efectuado um estudo imunol&#243;gico&#44; dirigido &#224; quantifica&#231;&#227;o das popula&#231;&#245;es e subpopula&#231;&#245;es linfocit&#225;rias&#58; CD3&#44; CD4&#44; CD8&#44; CD19&#44; CD56 e CD56CD8&#44; assim como dos receptores&#58; CD3CCR5&#44; CD4CCR5&#44; CD8CCR5&#44; CCR5M&#248;&#44; CXCR4&#44; CD3CXCR4&#44; CXCR4CD14 e da mol&#233;cula de co-esti-mula&#231;&#227;o CD28&#44; CD3CD28&#44; CD4CD28&#44; CD8CD28 atrav&#233;s de anticorpos monoclonais &#8211; CD8FITC&#44; CD19FITC&#44; CD3PE&#44; CD56PE&#44; CD4PECY5-Lymphogram Cytognos&#59; CCR5PE&#44; CXCRFITC-R &#38; D Systems&#59; CD8Cy5 e CD3Cy5 - DaKo&#44; CD4PE&#44; CD14PE&#44; CD28FITC &#8211; Immunotech&#59; CD4FITC-CLB&#44; CD8Percp &#8211; Beckton Dickinson e CD3 APC &#8211; Beckton Dickinson&#44; por cito-metria de fluxo &#40;<span class="elsevierStyleItalic">Facs Calibur-Beckton-Dickinson</span>&#41; a 3 ou 4 fluoresc&#234;ncias &#8211; FL1-FITC&#44; FL2-PE&#44; FL3-PECY&#44; FL4-APC&#46; Na an&#225;lise estat&#237;stica dos resultados foram utilizados os testes <span class="elsevierStyleItalic">t</span> -Student e de correla&#231;&#227;o linear&#46;</p><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Resultados&#58;</span> Salientamos os seguintes&#58; presen&#231;a do v&#237;rus no LLBA &#40;2&#44;95 log<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#44;08 log&#41;&#44; embora em quantidades inferiores &#224;s detectadas no sangue<span class="elsevierStyleHsp" style=""></span>&#40;5&#44;89 log<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#44;90&#41;<span class="elsevierStyleHsp" style=""></span>e grande varibilidade das cargas virais&#44; tanto no sangue como no LLBA&#44; independente do per&#237;odo de tempo entre o diagn&#243;stico e a realiza&#231;&#227;o do exame&#59; as popula&#231;&#245;es e subpopula&#231;&#245;es linfocit&#225;rias no sangue &#40;Quadro V&#41;&#44; em 13 doentes&#44; mostraram uma queda acentuada&#44; tanto dos linf&#243;citos totais como das suas popula&#231;&#245;es e subpopula&#231;&#245;es&#44; que atingia maior express&#227;o nas c&#233;lulas T-CD4&#46; Apenas em 2 casos &#40;doentes n&#46;<span class="elsevierStyleSup">os</span> 12 e 13&#41; esta subpopula&#231;&#227;o era superior a 250 c&#233;lulas&#47;mm<span class="elsevierStyleSup">3</span> e em 42&#44;9&#37; era inferior a 50 c&#233;lulas&#47;mm<span class="elsevierStyleSup">3</span>&#46; A popula&#231;&#227;o CD19 encontrava-se igualmente em n&#237;veis inferiores ao normal com uma distribui&#231;&#227;o individual se-melhante &#224; da subpopula&#231;&#227;o CD4&#46; Na maior parte dos casos&#44; a diminui&#231;&#227;o dos CD8 acompanhava a redu&#231;&#227;o dos CD4 e CD19<span class="elsevierStyleHsp" style=""></span>&#40;doentes n&#46;<span class="elsevierStyleSup">os</span> 7 e 8&#41;&#59; 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Tamb&#233;m no LLBA se verificou uma percentagem mais elevada de linf&#243;citos-T CD8 do que no sangue &#40;77&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&#44;6 &#47;67&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;2&#41;&#44; o que n&#227;o se observou em rela&#231;&#227;o &#224;s c&#233;lulas T-CD4 &#40;8&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#44;5 LLBA <span class="elsevierStyleItalic">vs&#46;</span>10&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#44;6 no sangue&#41;&#59; a actividade <span class="elsevierStyleItalic">natural killer</span> &#40;NK&#41; expressa pelas c&#233;lulas T CD56 apresentava importantes varia&#231;&#245;es individuais em ambos os meios&#44; mas com valores mais elevados no sangue do que no LLBA &#40;9&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#47;2&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;9&#41;&#59; quanto &#224; actividade citot&#243;xica avaliada atrav&#233;s das c&#233;lulas CD56CD8&#44; era similar no LLBA e no sangue &#40;2&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#47;1&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;2&#41;&#44; parecendo&#44; contudo&#44; que a distribui&#231;&#227;o individual era mais homog&#233;nea no primeiros destes meios &#40;Quadros VI e VII&#41;&#59; as c&#233;ulas duplamente negativas &#40;DN&#41; apresentavam-se com valores ligeiramente mais elevados no LLBA &#40;7&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;5 <span class="elsevierStyleItalic">vs</span> 5&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 5&#44;3&#41;&#46; Curiosamente&#44; neste meio observa-se uma percentagem elevada das c&#233;lulas menos diferenciadas &#40;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#44;6&#41; &#40;Quadro VI&#41;&#46; A an&#225;lise dos receptores celulares CCR5 e CXCR4 mostrou&#44; em termos globais e m&#233;dios&#44; diferentes comportamentos entre si e em rela&#231;&#227;o aos meios biol&#243;gicos &#40;Quadros VI e VII&#41;&#46; Assim&#44; o CCR5 CD3 era mais elevado no sangue &#40;10&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#44;2&#41; do que no LLBA &#40;8&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 3&#44;5&#41;&#59; no entanto&#44; o CCR5 CD4 e a CCR5 CD8 en-contravam-se em maior percentagem no LLBA do que no sangue &#40;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;3 e 4&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#44;7&#47;0&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;7 e 4&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;0 respec-tivamente&#41;&#46; No que diz respeito aos valores deste receptor na linha monoc&#237;tica-macrof&#225;gica ele apresentava-se muito mais elevados no LLBA &#40;77&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>41 no LLBA <span class="elsevierStyleItalic">vs&#46;</span> 18&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 15 no sangue&#41;&#46; Pelo contr&#225;rio&#44; o CXCR4 total era mais elevado no LLBA 31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#44;9&#41; do que no sangue &#40;16&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 8&#44;1&#41;&#59; esta tend&#234;ncia manisfestava-se igualmente em rela&#231;&#227;o aos linf&#243;citos-T &#40;26&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#44;8 <span class="elsevierStyleItalic">vs&#46;</span> 10&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;6&#41; e &#224; linha monoc&#237;tica-macrof&#225;gica&#44; ali&#225;s&#44; de uma forma exuberante &#40;84&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>30&#44;2 &#47; 4&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;6&#41;&#46; A actividade co-estimulat&#243;ria CD28 mostrou-se superior no sangue &#40;22&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#44;2&#41;<span class="elsevierStyleHsp" style=""></span>em compara&#231;&#227;o com o LLBA<span class="elsevierStyleHsp" style=""></span>&#40;15&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44;1&#41;<span class="elsevierStyleHsp" style=""></span>para as c&#233;lulas T totais&#44; CD4 e CD8<span class="elsevierStyleHsp" style=""></span>&#40;22&#44;5 16&#44;7&#59; 7&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;3&#59; 13&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;3 &#47; &#47; 16&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44;5&#59; 2&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;8&#59; 10&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;0&#44; respectivamente&#41;&#46;</p><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclus&#245;es&#58;</span><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="o0105"><span class="elsevierStyleLabel">1&#46;</span><p id="p0005" class="elsevierStylePara elsevierViewall">A infec&#231;&#227;o VIH &#233; repons&#225;vel por extensas e diversificadas altera&#231;&#245;es nos mecanismos de defesa do pulm&#227;o profundo&#46;</p></li><li class="elsevierStyleListItem" id="o0010"><span class="elsevierStyleLabel">2&#46;</span><p id="p0010" class="elsevierStylePara elsevierViewall">A complexa interac&#231;&#227;oo entre o hospedeiro e o agente agressor&#44; bem como a resposta imunol&#243;gica&#44; particularmente a <span class="elsevierStyleItalic">natural killer</span> e citot&#243;xica&#44; apoptose e doen&#231;as oportunistas&#44; ou outras&#44; podem dificultar a obten&#231;&#227;o de amostras m&#233;dicas homog&#233;neas&#46; Para al&#233;m disso&#44; considera&#231;&#245;es de ordem &#233;tica restringem&#44; natu-ralmente&#44; a abordagem destes doentes com finalidades exclusivamente cient&#237;ficas&#46;</p></li><li class="elsevierStyleListItem" id="o0015"><span class="elsevierStyleLabel">3&#46;</span><p id="p0015" class="elsevierStylePara elsevierViewall">Os resultados obtidos apontam tendencialmente para uma resposta pulmonar compartimentada &#224; agress&#227;o VIH&#44; com base na din&#226;mica celular envolvida e no perfil dos receptores encontrado nos l&#237;quidos biol&#243;gicos estudados&#46; Neste contexto&#44; esta compartimenta&#231;&#227;o parece estar particularmente na depend&#234;ncia da actividade dos macr&#243;fagos alveolares que constituem&#44; desde o in&#237;cio&#44; o eixo fundamental destes processos&#44; representando o &#250;lti-mo mecanismo celular de defesa deste territ&#243;rio&#44; quando os outros est&#227;o j&#225; profundamente alterados&#46;</p></li><li class="elsevierStyleListItem" id="o0025"><span class="elsevierStyleLabel">4&#46;</span><p id="p0030" class="elsevierStylePara elsevierViewall">O estudo da din&#226;mica dos receptores quimioc&#237;nicos pode vir a ter importantes implica&#231;&#245;es terap&#234;u-ticas&#46; De facto&#44; foi j&#225; demonstrado que o bloqueio do receptor CCR5 n&#227;o foi acompanhado por um aumento da express&#227;o do receptor CXCR4&#46; Neste estudo tivemos oportunidade de verificar que o CXCR4 se manteve elevado nas c&#233;lulas monoc&#237;ticas-macrof&#225;gicas durante a doen&#231;a&#44; aumentando a sua express&#227;o nos linf&#243;citos T nos doentes do Grupo II&#44; ao contr&#225;rio do comportamento do CCR5 no LLBA&#44; que dimi-nu&#237;a significativamente&#46; No sangue&#44; por&#233;m&#44; a express&#227;o do CCR5 aumentava&#46;</p></li><li class="elsevierStyleListItem" id="o0035"><span class="elsevierStyleLabel">5&#46;</span><p id="p0035" class="elsevierStylePara elsevierViewall">A elevada co-exist&#234;ncia de infec&#231;&#245;es oportunistas &#40;71&#44;4&#37;&#41; leva-nos a colocar a hip&#243;tese de que a modula&#231;&#227;o induzida pelos germes possa contribuir para a elevada express&#227;o do CXCR4&#46;</p></li><li class="elsevierStyleListItem" id="o0045"><span class="elsevierStyleLabel">6&#46;</span><p id="p0040" class="elsevierStylePara elsevierViewall">Finalmente&#44; esta t&#227;o marcada variabilidade individual tem indiscutivelmente implica&#231;&#245;es cl&#237;nicas&#46; Em termos gerais&#44; podemos dizer que&#44; para uma mais correcta abordagem terap&#234;utica&#44; cada doente deve ser pr&#233;via e individualmente analisado neste contexto&#46;</p></li></ul></p><p id="sp0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Rev Port Pneumol 2007&#59; XIII &#40;2&#41;&#58; 175-212</span></p></span>"
      ]
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0075" class="elsevierStyleSimplePara elsevierViewall">The course of HIV infection is accompanied by a wide individual variability&#46; The complex and large in-terplay between host and viral factors is crucial in the disease&#8217;s evolution&#46; The lung has been recognised from the beginning of the disease as one of the main targets of infectious and non-infectious complications of AIDS&#46; In this setting both anatomic and immunologic particularities of this organ play an important role&#46;</p><p id="sp0080" class="elsevierStyleSimplePara elsevierViewall">The hallmark of HIV is progressive immune dys-function&#46; Despite the intensive research into the pathogenesis&#44; several questions remain to be answered on the dynamic effects of HIV on pulmonary cells&#46; Previous studies in which we have participated sho-wed the early presence of lymphocytic alveolitis from the asymptomatic phase of infection&#46; Since then&#44; many collected data has brought new insights into the immune and biochemical mechanisms involving HIV cell entry&#44; as well as target cells&#44; cytokines and other cellular mediators&#46;</p><p id="sp0085" class="elsevierStyleSimplePara elsevierViewall">In this context&#44; the discovery that specific chemokine receptors could act as co-receptors for HIV&#44; allowed a better understanding of the mechanisms underlying viral cellular entry and tropism&#46; On this issue several authors have reported that in addition to the CD4 molecule&#44; most strains of HIV use the chemokine receptor CCR5 for viral attachment and entry into the host cells&#46; This receptor seems to be very important in disease transmission&#44; whereas CXCR4 receptor tends to be used by the viral strains that emerge later in the disease in addition to or instead of the CCR5&#46;</p><p id="sp0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Aims&#58;</span> To evaluate the pulmonary cellular dynamics in AIDS patients regarding the viral load in bronchoalveolar lavage fluid &#40;LLBA&#41;&#44; as well as cellularity and tropism through CCR5 and CXCR4 receptors&#46;</p><p id="sp0095" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material&#58;</span> 14 AIDS patients were enrolled in this study&#44; with a mean age of 39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;3<span class="elsevierStyleHsp" style=""></span>years &#40;9 males and 5 females&#41; all HIV1&#44; heterosexuals&#44; 6 smokers and 8 non-smokers&#44; none of them drug addicts&#46; These patients were referred to bronchoscopy with BAL&#44; for clinical suspicion of opportunistic lung infections&#46; These patients were later divided into two groups&#58; Group I &#40;recent diagnosis&#41; and Group II &#40;non-recent diagnosis&#41;&#46; While all patients had AIDS&#44; group I had also recent diagnosis of oportunistic infections and had not received yet anti-retroviral therapy whilst group II had a long-term disease evolution with several opportunistic episodes and anti-retroviral therapeutic&#46;</p><p id="sp0100" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Methods&#58;</span> BAL was performed both in the middle bronchus in diffuse or in other segmentar bronchus&#44; depending on radiographic abnormalities&#46; Plasma viral load was performed through PCR-RT in blood samples with EDTA&#44; centrifuged and frozen &#40;-80&#186; Cel-sius&#41; in the first 4 hours after being collected&#46; The viral load in BALf was quantified in 9 patients using the automatized Cobas Ampliprep&#47;Cobas Amplicor HIV1 Monitor TM Test&#44; version 1&#46;5 Roche Diagnostic Systems&#46; The results were expressed in a numeric scale&#44; with a dynamic variation of 50-750&#46;000 copies of RNA HIV1&#47;cm<span class="elsevierStyleSup">3</span> and later converted into a logarithmic scale&#46;</p><p id="sp0105" class="elsevierStyleSimplePara elsevierViewall">In 10 patients an immunological study was carried out in BALf and blood to quantify the lymphocyte populations and subsets &#40;CD3&#44; CD4&#44; CD8&#44; CD19&#44; CD56 and CD56CD8&#41; as well as the receptors CD3CCR5&#44; CD4CCR5&#44; CD8CCR5&#44; CCR5M&#248;&#44; CXCR4&#44; CD3CXCR4&#44; CXCR4CD14 and co-stimulatory molecule CD28&#44; CD3CD28&#44; CD4CD28&#44; CD8CD28 through monoclonal antibodies &#8211; CD8FITC&#44; CD19FITC&#44; CD3PE&#44; CD56PE&#44; CD4PECY5-Lymphogram Cytognos&#59; CCR5PE&#44; CXCRFITC-R &#38; D Systems&#59; CD8Cy5 and CD3Cy5-DaKo&#44; CD4PE&#44; CD14PE&#44; CD28FITC-Immunotech&#59; CD4FITC-CLB&#44; CD8Percp- Beckton Dickinson and CD3 APC &#8211; Beckton Dickinson&#44; by flow cytometry &#40;Facs Calibur-Be-ckton-Dickinson&#41; with 3 or 4 fluorescences &#8211; FL1-FITC&#44; FL2-PE&#44; FL3-PECY&#44; FL4-APC&#46; In the statistical analysis&#44; we used the Student <span class="elsevierStyleItalic">t</span>-test&#44; and linear correlation&#46;</p><p id="sp0110" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Results&#58;</span> Presence of HIV1 in BALf &#40;2&#46;95 log<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;08 log&#41;&#44; in small levels compared with plasma viral loads &#40;5&#46;89 log &#177;<span class="elsevierStyleHsp" style=""></span>5&#46;90 log&#41; &#40;Table IV&#41;&#46;There was great variability of viral loads in BALf as there was in blood independent of the time elapsed between diagnosis and the exam&#46;</p><p id="sp0115" class="elsevierStyleSimplePara elsevierViewall">As for the lymphocytic populations and subsets in blood &#40;Table V&#41; determined in 13 patients&#44; there was a significant fall of total lymphocytes as well as of their subsets&#44; although more marked in CD4 cells&#59; 42&#46;9&#37; had CD4 levels &#60; 50 cels&#47;mm<span class="elsevierStyleSup">3</span> and only 2 patients &#40;n&#186; 12&#44; 13&#41; had CD4<span class="elsevierStyleHsp" style=""></span>&#62; 250 cels&#47;mm<span class="elsevierStyleSup">3</span>&#46; The CD19 was reduced with an individual distribution similar to the CD4 subset&#46; In most cases&#44; the fall of CD8 accompanied the decrease of CD4 and CD19 &#40;patients-n&#186; 7 and 8&#41;&#46; The lymphocyte populations and subsets in BALf &#40;10 patients&#41; &#40;Table VI&#41; showed a percentual distribution similar to that observed in blood &#40;Table VII&#41; for CD3&#44; CD19&#44; CD4 and CD8 lymphocytes&#44; although the percentage of T cells was higher than in blood &#40;94&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5 &#47;84&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;4&#41; as opposed to B cells &#40;2&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3 &#47;10&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;6&#41;&#46; In BALf CD8<span class="elsevierStyleHsp" style=""></span>T cells were higher than in blood &#40;77&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&#46;6 &#47;67&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;2&#41;&#44; which was not observed for the CD4 lymphocytes &#40;8&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;5 BALf <span class="elsevierStyleItalic">vs&#46;</span>10&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;6 in blood&#41;&#46; The natural killer activity expressed by CD56<span class="elsevierStyleHsp" style=""></span>T cells had important indivi-dual variations in both biological fluids&#58; higher levels in blood than in BALf &#40;9&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8 &#47;2&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;9&#41;&#46; The cytotoxic activity of CD56CD8 was similar in blood and in BALf &#40;2&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2 &#47; 1&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;2&#41; while the individual distribution seemed more homogeneous in BALf &#40;Table VI&#41; than in blood &#40;Table VII&#41;&#46; The double-negative &#40;DN&#41; cells had slightly higher values in BALf &#40;7&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;5 <span class="elsevierStyleItalic">vs</span> 5&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;3&#41;&#46; Curiously&#44; in BALf we observed a higher percentage of less differenciated cells &#40;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;6&#41; &#40;Table VI&#41;&#46; The analysis of the receptors CCR5 and CXCR4 showed in general terms different behaviour concerning the two biological means &#40;Tables VI and VII&#41;&#46; Thus&#44; the CCR5 CD3 was hi-gher in blood &#40;10&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;2&#41; than in BALf &#40;8&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 3&#46;5&#41; while the CCR5 CD4 and CCR5 CD8 had an increased expression in BALf in relation to blood &#40;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3 and 4&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;7 &#47; 0&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;7 and 4&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;0 respectively&#41;&#46; Concerning the expression of this receptor on monocyte macrophage lineage a marked higher value was attained in BALft &#40;77&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 41 in BALf vs&#46; 18&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15 in blood&#41;&#46; On the contrary the total expression of CXCR4 was higher in BALf &#40;31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;9&#41; than in blood &#40;16&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 8&#46;1&#41;&#46; This tendency extended equally to the T lymphocytes &#40;26&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;8 vs&#46; 10&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;6&#41; and also to the monocyte-macrophage lineage in an exuberant manner &#40;84&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>30&#46;2 &#47; 4&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;6&#41;&#46; The co-stimulatory activity of CD28 showed higher values in blood &#40;22&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;2&#41; than in BALf &#40;15&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 10&#46;1&#41; for total T cells&#44; CD4 and CD8 lymphocytes 22&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;7&#59; 7&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;3&#59; 13&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;3 &#47; 16&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>&#177; 10&#46;5&#59; 2&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8&#59; 10&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;0 respectively&#41;&#46;</p><p id="sp0120" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclusions&#58;</span><ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="o0055"><span class="elsevierStyleLabel">1&#46;</span><p id="p0045" class="elsevierStylePara elsevierViewall">HIV infection is responsible for important and extensive abnormalities in lung host defences&#46;</p></li><li class="elsevierStyleListItem" id="o0065"><span class="elsevierStyleLabel">2&#46;</span><p id="p0060" class="elsevierStylePara elsevierViewall">The complex interaction between host and aggressor as well as the immune response particularly represented by natural killer and cytotoxic activities&#44; apoptosis&#44; and opportunistic diseases or others&#44; therapeutics and other factors may contibute to the difficulty in obtaining homogenous medical samples within research&#46; There are also ethical issues that restrict a purely scientific approach to these patients&#46;</p></li><li class="elsevierStyleListItem" id="o0075"><span class="elsevierStyleLabel">3&#46;</span><p id="p0065" class="elsevierStylePara elsevierViewall">These results point to a pulmonary response to HIV in a compartmentalised fashion according to the dynamic cellular elements involved and receptors in which the latter had distinct profiles related to the biological fluids&#46; In this context&#44; the lung compartimental response is particularly dependent on alveolar macrophages activity which is from the beginning the cornerstone of this process and is the last cellular defense mechanism in this territory when all others are profoundly affected&#46;</p></li><li class="elsevierStyleListItem" id="o0085"><span class="elsevierStyleLabel">4&#46;</span><p id="p0070" class="elsevierStylePara elsevierViewall">The dynamics of chemokines receptors may be very important in therapeutic approach as the blockage of the CCR5 receptor does not seem to trigger an increased expression of CXCR4 strains&#46; In fact&#44; we found that CXCR4 remained high in monocyte-macrophage cells throughout infection and its expression was increased in T-lymphocytes in Group II patients as opposed to CCR5 behavior in BALf which significantly decreases&#46; However&#44; in blood&#44; CCR5 expression increased&#44; unlike CXCR4&#46;</p></li><li class="elsevierStyleListItem" id="o0095"><span class="elsevierStyleLabel">5&#46;</span><p id="p0075" class="elsevierStylePara elsevierViewall">Due to high co-existing opportunistic infections &#40;71&#46;4&#37;&#41; we cannot ignore the hypothesis that this increased expression of CXCR4 was a result of the modulation induced by opportunistic agents&#46;</p></li><li class="elsevierStyleListItem" id="o0100"><span class="elsevierStyleLabel">6&#46;</span><p id="p0090" class="elsevierStylePara elsevierViewall">Finally&#44; this striking individual variability undoubtly has clinical implications&#46; This makes a case-by-case management strategy the correct approach&#46;</p></li></ul></p><p id="sp0150" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Rev Port Pneumol 2007&#59; XIII &#40;2&#41;&#58; 175-212</span></p></span>"
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Article information

ISSN: 08732159
Original language: Portuguese

DOI:10.1016/S0873-2159(15)30344-5

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	5	9	14
2024 October	36	28	64
2024 September	36	30	66
2024 August	62	29	91
2024 July	29	36	65
2024 June	19	16	35
2024 May	30	36	66
2024 April	23	24	47
2024 March	28	30	58
2024 February	40	10	50
2024 January	21	27	48
2023 December	23	28	51
2023 November	16	22	38
2023 October	9	26	35
2023 September	28	45	73
2023 August	14	21	35
2023 July	13	30	43
2023 June	28	13	41
2023 May	18	20	38
2023 April	18	11	29
2023 March	21	28	49
2023 February	19	22	41
2023 January	25	19	44
2022 December	34	19	53
2022 November	29	29	58
2022 October	34	27	61
2022 September	16	26	42
2022 August	32	50	82
2022 July	17	25	42
2022 June	10	20	30
2022 May	39	34	73
2022 April	26	31	57
2022 March	15	31	46
2022 February	19	21	40
2022 January	22	39	61
2021 December	21	24	45
2021 November	22	21	43
2021 October	16	30	46
2021 September	21	23	44
2021 August	22	22	44
2021 July	23	30	53
2021 June	15	18	33
2021 May	25	29	54
2021 April	65	52	117
2021 March	55	15	70
2021 February	40	20	60
2021 January	22	7	29
2020 December	23	17	40
2020 November	34	15	49
2020 October	29	8	37
2020 September	48	21	69
2020 August	46	24	70
2020 July	65	21	86
2020 June	40	22	62
2020 May	41	15	56
2020 April	47	13	60
2020 March	22	9	31
2020 February	34	26	60
2020 January	42	28	70
2019 December	27	12	39
2019 November	52	21	73
2019 October	28	17	45
2019 September	34	20	54
2019 August	43	19	62
2019 July	22	11	33
2019 June	30	13	43
2019 May	39	37	76
2019 April	22	22	44
2019 March	43	22	65
2019 February	23	20	43
2019 January	39	22	61
2018 December	14	11	25
2018 November	7	7	14
2018 October	7	0	7
2018 September	9	9	18
2018 August	43	24	67
2018 July	36	22	58
2018 June	41	16	57
2018 May	56	27	83
2018 April	72	28	100
2018 March	51	25	76
2018 February	48	11	59
2018 January	66	10	76
2017 December	99	22	121
2017 November	48	18	66
2017 October	32	16	48
2017 September	42	11	53
2017 August	33	17	50
2017 July	29	15	44
2017 June	27	9	36
2017 May	37	13	50
2017 April	8	7	15
2017 March	17	6	23
2017 February	9	5	14
2017 January	10	5	15
2016 December	16	7	23
2016 November	15	4	19
2016 October	11	9	20
2016 September	5	2	7
2016 August	4	3	7
2016 July	3	4	7
2016 May	1	4	5
2016 April	2	2	4
2016 March	5	9	14
2016 February	8	6	14
2016 January	12	2	14
2015 December	4	3	7
2015 November	3	1	4
2015 October	3	4	7

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