Background: Platelet activating factor (PAF) is a phospholipid synthesized by the action of phospholipase A2 and acetyl transferase. PAF possesses a wide range of biological activities. In the lung of the fetus and newborn, PAF binds to its G protein couple receptor to evoke its biological activities via a well-defined signaling pathway. High levels of PAF receptor (PAFr) activity in fetal ovine lung vascular smooth muscle cells (PVSMC) at baseline has previously been demonstrated, a finding that is further perpetuated by conditions of hypoxia similar to fetal lung environment. Additionally in fetal ovine PVSMC, a cross-talk between PAFr-mediated cell signaling and activity of the vasodilator cyclic nucleotides cGMP and cAMP acting via their respective receptors protein kinase (PK) G and PKA has been shown. The interaction of PAF with its receptor has been implicated in the pathogenesis of persistent pulmonary hypertension in the newborn (PPHN) which has a high incidence of hospitalization and death of newborn infants. Successful transition of fetus to newborn life entails a mechanism whereby vasoconstrictors necessary for fetal existence are abrogated in the immediate newborn. Hypothesis: We hypothesize that PPHN results from the failure to down regulate PAFr- mediated activity and /or failure to up-regulate activity of the vasodilators cGMP and cAMP. PPHN is triggered by chronic intrauterine or postnatal hypoxia. Then newborn PVSMC undergo hyperplasia and hypertrophy, which over time, results in irreversible vascular remodeling. Methods: My study aims to employ in vitro models to delineate the consequences of PAF-PAFr mediated pathway in the pharmacological effects of the cAMP-PKA and cGMP-PKG signaling and the involvement of this cross-talk in the pathogenesis of PPHN. I modeled my cell culture studies to mimic the low oxygen environment of fetal lungs (hypoxia), the normal oxygen environment of newborn lungs (normoxia) and high oxygen environment (hyperoxia) to which the newborn lung may be exposed in incidental clinical condition of PPHN. I studied the effect of PAF, a vasoconstrictor, cAMP/cGMP, vasodilators, and other inhibitors of the PAFr pathway on growth of newborn PVSMC, by DNA synthesis, and measured their effects on expression of mitogenic and non-mitogenic proteins. Results: We found that both hypoxia and hyperoxia decreased cell growth even in the presence of PAF which up-regulates cell growth in fetal PVSMC. Also PAF treatment of cells resulted in down regulation of the vasodilator proteins, PKA and PKG. Conclusion: Our data suggests that in the lung of the newborn a high activity of PAF-PAFr mediated activities will worsen the condition of PPHN imposed on the newborn lung by environmental or therapeutic conditions. We can speculate that, in the long run, these findings may translate into the establishment of less toxic protein-based management of PPHN.

Background: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. Objectives: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. Methods: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 ± 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. Results: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 ± 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 ± 0.5 to 2.6 ± 0.6, p < 0.01), peak oxygen consumption (from 12.5 ± 3.0 to 14.6 ± 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 ± 12 to 61 ± 18 beats/min, p < 0.001) and maximal workload (from 65 ± 21 to 80 ± 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. Conclusion: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Chronic myeloproliferative disorders (CMPD) seem to be associated with an increased risk for pulmonary hypertension (PH). Case Report: A patient with history of chronic idiopathic myelofibrosis (CIMF) presented with progressive dyspnea (New York Heart Association class III). Until this time he had not received specific treatment for CIMF. Echocardiography and rightheart catheterization confirmed PH. Further diagnostic procedures excluded a specific cause of PH. Therefore, primary PH was assumed. 2 years later he presented again with progressive dyspnea due to a progress of PH. A few days later the patient died from acute posterior myocardial infarction. Pathologic examination of the lung showed an obstruction of the small vessels by conglomerates of megakaryocytes. Discussion: We conclude that PH developed secondarily due to CMPD. PH should be suspected in patients with CMPD and should influence the decision for treatment of CMPD. / Hintergrund: Chronische myeloproliferative Erkrankungen (CMPD) scheinen mit einem erhöhten Risiko für pulmonale Hypertonie (PH) assoziiert zu sein. Kasuistik: Ein Patient mit chronisch idiopathischer Myelofibrose (CIMF) wurde aufgrund einer progressiven Belastungsdyspnoe (New York Heart Association Stadium III) überwiesen. Bis zu diesem Zeitpunkt erhielt er keine spezifische Behandlung seiner CIMF. Echokardiographie und Rechtsherzkatheter ergaben das Vorliegen einer PH. Eine spezifische Ursache der PH konnte zunächst ausgeschlossen werden. Somit wurde das Vorliegen einer primären PH vermutet. 2 Jahre später wurde der Patient mit erneut verschlechterter Belastungsdyspnoe vorgestellt, wobei ein Progress der PH feststellbar war. Einige Tage später verstarb der Patient an einem Hinterwandinfarkt. Die Autopsie des Lungengewebes zeigte einen Verschluss der kleinen Lungengefäße durch Konglomerate von Megakaryozyten. Diskussion: Die Entwicklung der PH ist bei diesem Patienten als Folge der CMPD einzuschätzen. Das Vorliegen einer PH bei Patienten mit CMPD sollte die Entscheidung zu spezifischen therapeutischen Maßnahmen hinsichtlich der CMPD beeinflussen. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung injury (CNLI) affecting infants of < 32 weeks gestation, which has a significant associated morbidity and mortality. The hallmarks of BPD as seen in the current era are arrested alveologenesis and parenchymal thickening. Those most severely affected may develop pulmonary hypertension which worsens the prognosis. No effective preventive therapy exists. Generation of damaging reactive oxygen species is implicated in its development. The more recently recognized reactive nitrogen species may also contribute to this disease. Thus, there is considerable interest in preventive antioxidant therapies, but results to date have not been promising. Newborn rats, exposed to 60% O2 for 14 days, develop a parenchymal injury and pulmonary hypertension that resembles the morphological features of human BPD. Previous studies have shown that following exposure to 60% O2, a pulmonary influx of neutrophils is followed by that of macrophages. Inhibiting the influx of neutrophils prevents the generation of reactive oxygen species, while simultaneously enhancing postnatal lung growth. Other interventions have shown that development of pulmonary hypertension is dependent upon increases in both 8-isoprostane and its downstream regulator of vascular tone, endothelin-1. Gentler ventilation strategies, incorporated to minimize induction of stretch-mediated pro-inflammatory cytokines, have shown benefits of permissive hypercapnia in adult lung injury. Multicentre clinical trials of permissive hypercapnia in neonates have not shown benefit. Therapeutic hypercapnia has been demonstrated to have a protective effect of PaCO2 in both acute studies of ventilator-induced and ischemia-reperfusion injuries in animal models. In the studies reported herein, therapeutic hypercapnia was found to completely protect against CNLI and attenuate 60% O2-induced macrophage-derived protein nitration. The likely nitrating agent was macrophage-derived peroxynitrite. The critical role of peroxynitrite, in the development of chronic neonatal lung injury in this model, was confirmed using a peroxynitrite decomposition catalyst. This protected against the impairments of alveolarization and of pulmonary vascularization induced by 60% O2. These results suggest a more significant role for reactive nitrogen species than previously recognized. Finally, preliminary evidence is presented supporting a role for neutrophil-derived elastase in initiating the macrophage influx in the lungs, required for peroxynitrite generation, during 60% O2-mediated injury.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

La circulation pulmonaire est un système à faible pression (entre 10 et 15 mmHg au repos). Son principal rôle est la ré-oxygénation du sang qui permet l’apport aux organes du dioxygène nécessaire à leur fonctionnement. L’hyperTension Pulmonaire (HTP) est l’une de ses principales pathologies. Il s’agit d’une maladie rare engageant le pronostic vital du patient, définie par une pression artérielle pulmonaire moyenne supérieure ou égale à 25 mmHg au repos. Elle s’explique par une augmentation des résistances vasculaires pulmonaires liée, entre autres, au remodelage artériel présent dans cette pathologie participant à la diminution de la lumière artérielle. En effet, chez les patients atteint d’HTP, les trois tuniques formant l’artère (intima-media-adventice) voient leur structure se modifier. La plupart des travaux portent sur le remodelage de la media, mais de plus en plus d’études montrent que les premières altérations observées se situent au niveau de l’adventice. Plus précisément, les fibroblastes, les cellules majoritaires de cette tunique, agiraient comme régulateur clé de la fonction vasculaire pulmonaire. En réponse à un stress extérieur tel que l’hypoxie (à l’origine de certaines formes d'HTP), elles seraient les premières cellules à s’activer d'où leur dénomination par certains de « cellules sentinelles ». Cette activation se manifeste entre autres par des changements phénotypiques (différenciation en myofibroblastes), leur prolifération, leur migration, et la surproduction de protéines de la matrice extracellulaire. Ainsi les fibroblastes participent directement au remodelage artériel global observé dans l’HTP. Le calcium est connu pour réguler un grand nombre de voies de signalisation cellulaire impliquées dans les phénomènes précédemment cités. Au laboratoire, l’implication du canal TRPV4 (Transient Receptor Potential Vanilloid 4), un canal non sélectif perméable aux ions Ca2+, a déjà été montré concernant le remodelage de la media. L’activation du canal, amplifiée en situations pathologiques, participe à la migration et à la prolifération des cellules musculaires lisses des artères pulmonaires. Aussi, des données de la littérature montrent que TRPV4 joue un rôle important dans l’activité délétère des fibroblastes dans les sclérodermies, les fibroses pulmonaire et cardiaque. Il nous a donc semblé intéressant d’étudier l’implication des fibroblastes et du canal TRPV4 dans le remodelage adventitiel artériel lors de l’hypertension pulmonaire. Pour ce faire, nous nous sommes intéressés, dans une première partie, à l’implication du canal TRPV4 dans ce remodelage au niveau tissulaire. Nous avons ainsi montré, à l’aide de deux modèles animaux hypertendus, un induit par l’injection de monocrotaline et l’autre induit par une exposition hypoxique chronique, que la protéine TRPV4 est surexprimée dans l’adventice alors que son remodelage est significativement atténué chez des souris invalidées pour le gène trpv4. Dans un second temps, nous avons alors étudié le rôle de ce canal dans les réponses cellulaires impliquées dans le remodelage adventitiel. Pour cela nous avons mis au point la culture de fibroblastes d'adventice d'artères intrapulmonaires de rats. Puis par une approche pharmacologique (activateurs et bloqueurs du canal) et à l’aide de siRNA, nous avons montré que l’activation du canal TRPV4 favorise la prolifération (par incorporation de BrdU) et la migration (par test de brèche) des fibroblastes, ainsi que leur activité profibrotique avec la surproduction de matrice extracellulaire (MEC) (par quantification de l’expression protéique par Western blot). Il serait désormais intéressant de cultiver les fibroblastes en mimant in vitro les conditions pathologiques, en les plaçant dans un environnement hypoxique et/ou en les soumettant à un étirement chronique, et d’évaluer l’impact de l’HTP sur le canal et ses actions cellulaires. / Pulmonary circulation is a low pressure system (between 10 and 15 mmHg at rest). Its first role is blood oxygenation which allows to carry dioxygen to the organs fontionnality. Pulmonary Hypertension (PH) is one of the main pulmonary diseases. It is a rare and potentially fatal disorder, defined by a high arterial pulmonary mean pressure (greater than or equal to 25 mmHg at rest). This high pressure can be explained by the elevation of pulmonary arterial resistance and related to narrowing of the lumen of the artery, induced, among other, by the arterial remodeling in this pathology. Indeed, during the pathology implementation, the structure of the all three layers constituting the artery wall (intima-media-adventitia) is altered. The media and intima have received much attention from vascular biologists, howewer an increasing volume of experimental data indicates that this third compartment undergoes earlier and dramatic remodeling during PH. More specifically, the fibroblasts, the most abundant cells in adventitia, may act as key regulator of pulmonary vascular wall structure and function from the "outside-in". The fibroblasts may play the role of “sentinel cell” in the vessel wall. In responding to various stimuli, these cells are the first artery wall cells to show evidence of “activation” as proliferation, myofibroblast differenciation, migrationand invasion in the other wall layer, and extracellular matrix production. That way, fibroblasts participate directly to the overall artery remodeling observed in PH. Calcium is involved in numerous cellular signalling pathways such as those previously described. In the laboratory, we already proved that TRPV4 (Transient Receptor Potential Vanilloid) channel, a non-selective cationic channel calcium permeable, is involved in media remodeling. Moreover, several datas show that this channel play an important role in diseases in which we observe a negative role of fibroblast such as sclerodermia, cardiac and pulmonary fibrosis. Considering these results, we were interested in the role of TRPV4 in fibroblast during PH more precisely in the adventitial remodeling process observed in this pathology. We first demonstrated the involment of TRPV4 in the adventitia remodeling regarding the tissue. Using two different animal models of PH, chronic hypoxia and monocrotalin models, we identified that this protein was up-regulated in sick rats and the mouse knock-down for this gene developed attenuated PH and adventitia remodeling compare to the control. Then we studied the role of TRPV4 in the mechanism leading to the adventitia remodeling. Thanks to pharmacological molecule and siRNA we proved that activation of TRPV4 increased proliferation (BrdU assay), migration (wound assay) and fibrotic activity such as excessed production of extracellular matrix (using western blot analyse) of the fibroblasts. With all these results, it would be interested to culture fibroblasts in hypoxic conditions and/or subjecting themselves to chronicle stretch to imitate HTP pathology and evaluate TRPV4 role in these conditions

Introdução: Em pacientes com fibrose cística (FC), as infecções pulmonares de repetição e a inflamação com acúmulo de secreções causam obstrução aérea e hiperinsuflação. Com a progressão da doença, esses pacientes desenvolvem doença pulmonar incapacitante, falência respiratória, hipertensão pulmonar (HP) e cor pulmonale. Os avanços no tratamento propiciaram uma melhora acentuada na sobrevida dos pacientes: atualmente expectativa de vida média é de mais de 40 anos. Essa modificação demográfica resultou na necessidade de programas e protocolos de cuidados específicos para os pacientes adultos com FC. Objetivos: Este estudo visa avaliar desfechos clínicos e fatores prognósticos em uma coorte de pacientes adultos com FC durante sete anos de seguimento. Secundariamente, objetivou-se avaliar alterações no escore clínico, na espirometria, no teste de caminhada de seis minutos (TC6M) e na pressão arterial pulmonar pela pressão sistólica da artéria pulmonar (PSAP) estimada por ecocardiograma Doppler. Métodos: Observou-se uma coorte prospectiva de pacientes com FC, acompanhados por programa para adultos em 2004-2005. Realizaram-se avaliação clínica, Doppler ecocardiografia, espirometria, TC6M, raio X de tórax, e culturas de escarro. Os desfechos foram definidos como favorável (sobreviventes) e desfavorável (sobreviventes com transplante pulmonar e óbitos). Em 2011-2012, os desfechos foram avaliados, e os sobreviventes reexaminados. Resultados: De 40 pacientes (média de idade 23,7 ± 6,3 anos) estudados, 32 (80%) foram sobreviventes, 2 (5%) sobreviventes com transplante pulmonar e 6 (15%) morreram. Análise de regressão logística identificou volume expiratório forçado no primeiro segundo (VEF1) % previsto (odds ratio - OR=0,83, intervalo de confiança - IC=0,67-1,03, p=0,09) e PSAP (OR=0,70, IC=1,02-2,01, p=0,038) associados ao desfecho desfavorável. VEF1 ≤ 30% previsto teve sensibilidade, especificidade, valores preditivos positivos e negativos, respectivamente de 50%, 93,8%, 66,7% e 88,2%; e PSAP ≥ 42mmHg, respectivamente, de 62,5%, 93,1%, 71,4% e 90%. Após sete anos, houve deterioração no escore clínico (p=0,027), na capacidade vital forçada (CVF) (p=0,024), no VEF1 (p<0,001), na distância percorrida no TC6M (p=0,002), na saturação de oxigênio periférica (SpO2) basal (p<0,001) e na SpO2 final (p<0,001). Conclusão: Após sete anos de seguimento, observou-se desfecho desfavorável em 20% dos pacientes. Os preditores prognósticos mais significativos foram PSAP ≥ 42mmHg e VEF1 ≤ 30% do previsto. Ocorreu expressiva deterioração clínica e funcional nos sobreviventes. / Introduction: In patients with cystic fibrosis (CF), the continuous pulmonary infection and inflammation with thickened secretions cause airways obstruction and hyperinflation. As the disease progresses, these patients develop disabling lung disease and eventually respiratory failure, pulmonary hypertension, and cor pulmonale. Advances in medical therapy have resulted in a dramatic improvement in survival such that nowadays the median survival is predicted to be greater than 40 years. This demographic shift has resulted in the need for adult-specific CF care programs and protocols. Objectives: To evaluate clinical outcomes and prognostic factors in a cohort of adult CF patients during a seven years follow-up. Secondarily, to evaluate changes in clinical score, spirometry, six minute walk test (6MWT) and pulmonary arterial pressure by pulmonary artery systolic pressure (PASP) estimated by Doppler ecochardiography. Methods: a prospective cohort of CF patients attending to an adult program during 2004-2005. Patients underwent clinical evaluation, Doppler echocardiography, spirometry, 6MWT, chest X rays and sputum cultures. Outcomes were defined as good outcome (survival) and poor outcome (survival with lung transplantation and death). In 2011-2012 outcomes were evaluated and survivors were reexamined. Results: Out of 40 patients (mean age of 23.7 ± 6.3 years) studied, 32 (80%) were survivors, 2 (5%) were survivors with lung transplantation and 6 (15%) died. Logistic regression analysis identified forced expiratory volume in first second (FEV1) % predicted (odds ratio - OR=0.83, confidence interval - CI=0.67-1.03, p=0.09) and PASP (OR=0.70, CI=1.02-2.01, p=0.038) associated with poor outcome. The FEV1 ≤ 30% predicted had sensitivity, specificity, positive and negative predictive value of, respectively, 50%, 93.8%, 66.7%, and 88.2%; and the PASP ≥ 42mmHg, respectively, 62.5%, 93.1%, 71.4%, and 90%. In 7 years follow-up, deterioration was observed in clinical score (p=0.027), forced vital capacity (p=0.024), FEV1 (p<0.001), distance walked in 6MWT (p=0.002), basal peripheral oxygen saturation (SpO2) (p<0.001) and final SpO2 (p<0.001). Conclusion: After seven years of follow-up, poor outcome was reported in 20% of CF patients. PASP ≥ 42 mmHg and FEV1 ≤ 30% predicted were the most significant prognostic predictors. Clinical and functional deterioration was observed in survivors.

Submitted by THALITA LEONE ALVES ROCHA null (thalarocha@hotmail.com) on 2016-04-18T15:51:39Z No. of bitstreams: 1 dissertação thalita final.pdf: 794073 bytes, checksum: 8f42b335b8638b50194b64ede638c446 (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-04-19T16:16:26Z (GMT) No. of bitstreams: 1 rocha_tla_me_bot.pdf: 794073 bytes, checksum: 8f42b335b8638b50194b64ede638c446 (MD5) / Made available in DSpace on 2016-04-19T16:16:26Z (GMT). No. of bitstreams: 1 rocha_tla_me_bot.pdf: 794073 bytes, checksum: 8f42b335b8638b50194b64ede638c446 (MD5) Previous issue date: 2016-02-29 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / As metaloproteinases de matriz extracelular (MMPs) podem limitar a vasodilatação pulmonar e os efeitos inotrópicos positivos promovidos pela adrenomedulina durante a hipertensão pulmonar. O presente estudo teve por objetivo avaliar os efeitos da administração combinada da doxiciclina (inibidor não seletivo das MMPs) e da adrenomedulina sobre as alterações hemodinâmicas observadas durante a embolia pulmonar aguda em ovinos. Alterações hemodinâmicas e respiratórias foram mensuradas em ovinos anestesiados, pré-tratados com doxiciclina (10 mg/kg por via intravenosa), submetidos à EPA induzida pela injeção intravenosa (IV) de microesferas de silicone (500 mg) e posteriormente tratados com solução salina (grupo Dox+PE) ou adrenomedulina (50 ng/kg/min) (grupo Dox+PE+Adm). Os resultados deste estudo foram comparados com grupos históricos recentemente publicados por nosso grupo de pesquisa, realizados sob as mesmas condições experimentais, onde foram utilizados ovinos anestesiados não submetidos a qualquer intervenção (grupo Sham) ou submetidos à EPA e tratados com solução salina (grupo PE) ou com adrenomedulina (50 ng/kg/min) (grupo PE+Adm). Doxiciclina não produziu efeitos adicionais sobre as diminuições significativas no índice de resistência vascular pulmonar e aumento no índice cardíaco (ambos em 25%) observadas com o uso da adrenomedulina (grupo PE+Adm). A administração da adrenomedulina (grupo PE+Adm e Dox+PE+Adm) diminuiu significativamente a pressão arterial média e o índice de resistência vascular sistêmica, levando a uma hipotensão sistêmica moderada. Reduções significativas na pressão parcial de oxigênio arterial foram observadas após a doxiciclina e a EPA, que não foram afetadas pela administração da adrenomedulina. Estes resultados demonstram que a administração combinada da doxiciclina e adrenomedulina não traz benefícios hemodinâmicos adicionais quando comparada ao uso isolado da adrenomedulina, sugerindo que está combinação não se apresenta vantajosa durante a EPA induzida por microesferas. / Matrix metalloproteinases (MMPs) may limit severely the pulmonary vasodilatory and inotropic effects of adrenomedullin during pulmonary hypertension. Hemodynamic and respiratory changes were measured in anesthetized bovine pre-treated with doxycycline (10 mg/kg intravenously), subjected to APE induced by intravenous injection of silicone microspheres (500 mg) and subsequently treated with physiological saline (Dox+PE group) or adrenomedullin (50 ng / kg / min) (Dox+PE+ Adm group). The results were compared with historical group recently published by our research group, carried out under the same experimental conditions, where anesthetized sheep were used not subjected to any intervention (Sham group) or subjected to APE, and treated with physiological saline (PE group) or with adrenomedullin (50 ng / kg / min) (PE+Adm Group). Doxycycline produced no effect on significant temporal decreases in pulmonary vascular resistance index and increases in cardiac index (both by 25%) observed with adrenomedullin. The administration of adrenomedullin significantly decreased mean arterial pressure and systemic vascular resistance index, leading to a moderate systemic hypotension. Significant decreases in arterial oxygen partial pressure were observed after doxycycline or APE, but these changes were not affected by adrenomedullin. These results demonstrate that the combined administration of doxycycline and adrenomedullin does not provide additional hemodynamic benefits when compared to isolated use of adrenomedullin, suggesting that this combination does not appear advantageous for the APE-induced microspheres. / FAPESP: 2012/12.291-7

Orientador: Carlos Alan Candido Dias Junior / Resumo: As metaloproteinases de matriz extracelular (MMPs) podem limitar a vasodilatação pulmonar e os efeitos inotrópicos positivos promovidos pela adrenomedulina durante a hipertensão pulmonar. O presente estudo teve por objetivo avaliar os efeitos da administração combinada da doxiciclina (inibidor não seletivo das MMPs) e da adrenomedulina sobre as alterações hemodinâmicas observadas durante a embolia pulmonar aguda em ovinos. Alterações hemodinâmicas e respiratórias foram mensuradas em ovinos anestesiados, pré-tratados com doxiciclina (10 mg/kg por via intravenosa), submetidos à EPA induzida pela injeção intravenosa (IV) de microesferas de silicone (500 mg) e posteriormente tratados com solução salina (grupo Dox+PE) ou adrenomedulina (50 ng/kg/min) (grupo Dox+PE+Adm). Os resultados deste estudo foram comparados com grupos históricos recentemente publicados por nosso grupo de pesquisa, realizados sob as mesmas condições experimentais, onde foram utilizados ovinos anestesiados não submetidos a qualquer intervenção (grupo Sham) ou submetidos à EPA e tratados com solução salina (grupo PE) ou com adrenomedulina (50 ng/kg/min) (grupo PE+Adm). Doxiciclina não produziu efeitos adicionais sobre as diminuições significativas no índice de resistência vascular pulmonar e aumento no índice cardíaco (ambos em 25%) observadas com o uso da adrenomedulina (grupo PE+Adm). A administração da adrenomedulina (grupo PE+Adm e Dox+PE+Adm) diminuiu significativamente a pressão arterial média e o índice ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Matrix metalloproteinases (MMPs) may limit severely the pulmonary vasodilatory and inotropic effects of adrenomedullin during pulmonary hypertension. Hemodynamic and respiratory changes were measured in anesthetized bovine pre-treated with doxycycline (10 mg/kg intravenously), subjected to APE induced by intravenous injection of silicone microspheres (500 mg) and subsequently treated with physiological saline (Dox+PE group) or adrenomedullin (50 ng / kg / min) (Dox+PE+ Adm group). The results were compared with historical group recently published by our research group, carried out under the same experimental conditions, where anesthetized sheep were used not subjected to any intervention (Sham group) or subjected to APE, and treated with physiological saline (PE group) or with adrenomedullin (50 ng / kg / min) (PE+Adm Group). Doxycycline produced no effect on significant temporal decreases in pulmonary vascular resistance index and increases in cardiac index (both by 25%) observed with adrenomedullin. The administration of adrenomedullin significantly decreased mean arterial pressure and systemic vascular resistance index, leading to a moderate systemic hypotension. Significant decreases in arterial oxygen partial pressure were observed after doxycycline or APE, but these changes were not affected by adrenomedullin. These results demonstrate that the combined administration of doxycycline and adrenomedullin does not provide additional hemodynamic benefits when compared to iso... (Complete abstract click electronic access below) / Mestre

Introdução: Em pacientes com fibrose cística (FC), as infecções pulmonares de repetição e a inflamação com acúmulo de secreções causam obstrução aérea e hiperinsuflação. Com a progressão da doença, esses pacientes desenvolvem doença pulmonar incapacitante, falência respiratória, hipertensão pulmonar (HP) e cor pulmonale. Os avanços no tratamento propiciaram uma melhora acentuada na sobrevida dos pacientes: atualmente expectativa de vida média é de mais de 40 anos. Essa modificação demográfica resultou na necessidade de programas e protocolos de cuidados específicos para os pacientes adultos com FC. Objetivos: Este estudo visa avaliar desfechos clínicos e fatores prognósticos em uma coorte de pacientes adultos com FC durante sete anos de seguimento. Secundariamente, objetivou-se avaliar alterações no escore clínico, na espirometria, no teste de caminhada de seis minutos (TC6M) e na pressão arterial pulmonar pela pressão sistólica da artéria pulmonar (PSAP) estimada por ecocardiograma Doppler. Métodos: Observou-se uma coorte prospectiva de pacientes com FC, acompanhados por programa para adultos em 2004-2005. Realizaram-se avaliação clínica, Doppler ecocardiografia, espirometria, TC6M, raio X de tórax, e culturas de escarro. Os desfechos foram definidos como favorável (sobreviventes) e desfavorável (sobreviventes com transplante pulmonar e óbitos). Em 2011-2012, os desfechos foram avaliados, e os sobreviventes reexaminados. Resultados: De 40 pacientes (média de idade 23,7 ± 6,3 anos) estudados, 32 (80%) foram sobreviventes, 2 (5%) sobreviventes com transplante pulmonar e 6 (15%) morreram. Análise de regressão logística identificou volume expiratório forçado no primeiro segundo (VEF1) % previsto (odds ratio - OR=0,83, intervalo de confiança - IC=0,67-1,03, p=0,09) e PSAP (OR=0,70, IC=1,02-2,01, p=0,038) associados ao desfecho desfavorável. VEF1 ≤ 30% previsto teve sensibilidade, especificidade, valores preditivos positivos e negativos, respectivamente de 50%, 93,8%, 66,7% e 88,2%; e PSAP ≥ 42mmHg, respectivamente, de 62,5%, 93,1%, 71,4% e 90%. Após sete anos, houve deterioração no escore clínico (p=0,027), na capacidade vital forçada (CVF) (p=0,024), no VEF1 (p<0,001), na distância percorrida no TC6M (p=0,002), na saturação de oxigênio periférica (SpO2) basal (p<0,001) e na SpO2 final (p<0,001). Conclusão: Após sete anos de seguimento, observou-se desfecho desfavorável em 20% dos pacientes. Os preditores prognósticos mais significativos foram PSAP ≥ 42mmHg e VEF1 ≤ 30% do previsto. Ocorreu expressiva deterioração clínica e funcional nos sobreviventes. / Introduction: In patients with cystic fibrosis (CF), the continuous pulmonary infection and inflammation with thickened secretions cause airways obstruction and hyperinflation. As the disease progresses, these patients develop disabling lung disease and eventually respiratory failure, pulmonary hypertension, and cor pulmonale. Advances in medical therapy have resulted in a dramatic improvement in survival such that nowadays the median survival is predicted to be greater than 40 years. This demographic shift has resulted in the need for adult-specific CF care programs and protocols. Objectives: To evaluate clinical outcomes and prognostic factors in a cohort of adult CF patients during a seven years follow-up. Secondarily, to evaluate changes in clinical score, spirometry, six minute walk test (6MWT) and pulmonary arterial pressure by pulmonary artery systolic pressure (PASP) estimated by Doppler ecochardiography. Methods: a prospective cohort of CF patients attending to an adult program during 2004-2005. Patients underwent clinical evaluation, Doppler echocardiography, spirometry, 6MWT, chest X rays and sputum cultures. Outcomes were defined as good outcome (survival) and poor outcome (survival with lung transplantation and death). In 2011-2012 outcomes were evaluated and survivors were reexamined. Results: Out of 40 patients (mean age of 23.7 ± 6.3 years) studied, 32 (80%) were survivors, 2 (5%) were survivors with lung transplantation and 6 (15%) died. Logistic regression analysis identified forced expiratory volume in first second (FEV1) % predicted (odds ratio - OR=0.83, confidence interval - CI=0.67-1.03, p=0.09) and PASP (OR=0.70, CI=1.02-2.01, p=0.038) associated with poor outcome. The FEV1 ≤ 30% predicted had sensitivity, specificity, positive and negative predictive value of, respectively, 50%, 93.8%, 66.7%, and 88.2%; and the PASP ≥ 42mmHg, respectively, 62.5%, 93.1%, 71.4%, and 90%. In 7 years follow-up, deterioration was observed in clinical score (p=0.027), forced vital capacity (p=0.024), FEV1 (p<0.001), distance walked in 6MWT (p=0.002), basal peripheral oxygen saturation (SpO2) (p<0.001) and final SpO2 (p<0.001). Conclusion: After seven years of follow-up, poor outcome was reported in 20% of CF patients. PASP ≥ 42 mmHg and FEV1 ≤ 30% predicted were the most significant prognostic predictors. Clinical and functional deterioration was observed in survivors.