Controversy surrounding the increased expression of TGFβ1 in asthma

Asthma is a waxing and waning disease that leads to structural changes in the airways, such as subepithelial fibrosis, increased mass of airway smooth muscle and epithelial metaplasia. Such a remodeling of the airways futher amplifies asthma symptoms, but its etiology is unknown. Transforming growth factor β1 is a pleiotropic cytokine involved in many fibrotic, oncologic and immunologic diseases and is believed to play an essential role in airway remodeling that occurs in asthmatic patients. Since it is secreted in an inactive form, the overall activity of this cytokine is not exclusively determined by its level of expression, but also by extensive and complex post-translational mechanisms, which are all importanin modulating the magnitude of the TGFβ1 response. Even if TGFβ1 upregulation in asthma is considered as a dogma by certain investigators in the field, the overall picture of the published litterature is not that clear and the cellular origin of this cytokine in the airways of asthmatics is still a contemporaneous debate. On the other hand, it is becoming clear that TGFβ1 signaling is increased in the lungs of asthmatics, which testifies the increased activity of this cytokine in asthma pathogenesis. The current work is an impartial and exhaustive compilation of the reported papers regarding the expression of TGFβ1 in human asthmatics. For the sake of comparison, several studies performed in animal models of the disease are also included. Inconsistencies observed in human studies are discussed and conclusions as well as trends from the current state of the litterature on the matter are proposed. Finally, the different points of regulation that can affect the amplitude of the TGFβ1 response are briefly revised and the possibility that TGFβ1 is disregulated at another level in asthma, rather than simply in its expression, is highlighted

Psoríase moderada a grave tratada com infliximabe em 53 pacientes: perfil dos pacientes, eficácia e efeitos adversos Moderate to severe psoriasis treated with infliximab - 53 patients: patients profile, efficacy and adverse effects

FUNDAMENTOS: A psoríase leva a um impacto negativo significativo na qualidade de vida e está associada a comorbidades. A atividade inflamatória das placas psoríacas se inicia, em parte, pela ativação de linfócitos Th1, que liberam citocinas pró-inflamatórias, como TNF alfa. Infliximabe neutraliza a atividade biológica do TNF alfa. Reações adversas que ocorrem durante a infusão e até 24 horas após são chamadas de agudas. Reações tardias ocorrem entre 24 horas e 14 dias após infusão. OBJETIVO: Avaliar o perfil dos pacientes com psoríase moderada a grave e resistente ao tratamento convencional, bem como as reações adversas ao infliximabe. MÉTODO: Foram tratados com infliximabe 53 pacientes: 40 homens e 13 mulheres. A dose utilizada foi 5 mg/kg nas semanas 0, 2 e 6 (fase de indução), seguida da fase de manutenção a cada oito semanas. RESULTADO: Dentre os 53 pacientes, seis se submeteram apenas à fase de indução, obtiveram Pasi 90-100 e não receberam mais a droga. Quarenta e sete pacientes continuaram recebendo a medicação por pelo menos dois, três anos. Deles, 55,3% (26) apresentaram algum efeito adverso. Os efeitos adversos precoces foram observados em 34% dos pacientes, e os tardios, em 36,1% dos pacientes. Foi encontrada uma prevalência de 57,4% de comorbidades nesses pacientes. CONCLUSÃO: O infliximabe mostrou-se seguro e eficaz no presente estudo. Dentre as comorbidades associadas aos pacientes neste estudo, a obesidade se relacionou com uma resposta mais tardia e menos eficiente. Efeitos adversos precoces e tardios, quando bem monitorados, não impedem a manutenção da terapêutica e não expõem os pacientes a riscos não controlados.<br>BACKGROUND: Psoriasis exerts a significant negative effect on quality of life and is associated with comorbidities. The inflammatory activity of the psoriasis plaques is partially triggered by activation of the Th1 lymphocytes, which release proinflammatory cytokines such as TNF-alpha. Infliximab neutralizes the biological activity of TNF-alpha. Adverse reactions that occur during infusion or up to 24 hours afterwards are referred to as acute reactions. Delayed reactions are those occurring between 24 hours and 14 days after an infusion. OBJECTIVE: To evaluate the profile of patients with moderate to severe psoriasis that is resistant to conventional treatment, and to assess adverse reactions to infliximab. METHODS: Fifty-three patients, 40 men and 13 women, were treated with infliximab. The dose used was 5 mg/kg in weeks 0, 2 and 6 (induction phase), followed by maintenance therapy every 8 weeks. RESULTS: Of the 53 patients, 6 participated only in the induction phase. These patients reached Psoriasis Area Severity Index (PASI) of 90-100 and opted to discontinue treatment. Forty-seven patients continued therapy with the drug for at least 2-3 years. Of these, 55.3% (n=26) experienced some type of adverse event. Acute adverse events were recorded in 34% of the patients and delayed adverse events in 36.1%. The prevalence of comorbidities was 57.4%. CONCLUSION: In the present study, infliximab was found to constitute a safe and effective form of therapy. Of the comorbidities recorded in the patients in this study, obesity was associated with a delayed and less effective response to treatment. When adequately monitored, neither acute nor delayed adverse events require discontinuation of therapy, since they do not represent an uncontrolled risk to the patient

Estrogen Preserves Pulsatile Pulmonary Arterial Hemodynamics in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is caused by extensive pulmonary vascular remodeling that increases right ventricular (RV) afterload and leads to RV failure. PAH predominantly affects women; paradoxically, female PAH patients have better outcomes than men. The roles of estrogen in PAH remain controversial, which is referred to as “the estrogen paradox”. Here, we sought to determine the role of estrogen in pulsatile pulmonary arterial hemodynamic changes and its impact on RV functional adaption to PAH. Female mice were ovariectomized and replenished with estrogen or placebo. PAH was induced with SU5416 and chronic hypoxia (SuHx). In vivo hemodynamic measurements showed that (1) estrogen prevented loss of pulmonary vascular compliance with limited effects on the increase of pulmonary vascular resistance in PAH; (2) estrogen attenuated increases in wave reflections in PAH and limited its adverse effects on PA systolic and pulse pressures; and (3) estrogen maintained the total hydraulic power and preserved transpulmonary vascular efficiency in PAH. This study demonstrates that estrogen preserves pulmonary vascular compliance independent of pulmonary vascular resistance, which provides a mechanical mechanism for ability of estrogen to delay disease progression without preventing onset. The estrogenic protection of pulsatile pulmonary hemodynamics underscores the therapeutic potential of estrogen in PAH