Immunohistological features related to functional impairment in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterized by the pulmonary infiltration of smooth muscle-like cells (LAM cells) and cystic destruction. Patients usually present with airway obstruction in pulmonary function tests (PFTs). Previous studies have shown correlations among histological parameters, lung function abnormalities and prognosis in LAM. We investigated the lung tissue expression of proteins related to the mTOR pathway, angiogenesis and enzymatic activity and its correlation with functional parameters in LAM patients. METHODS: We analyzed morphological and functional parameters of thirty-three patients. Two groups of disease severity were identified according to FEV1 values. Lung tissue from open biopsies or lung transplants was immunostained for SMA, HMB-45, mTOR, VEGF-D, MMP-9 and D2-40. Density of cysts, density of nodules and protein expression were measured by image analysis and correlated with PFT parameters. RESULTS: There was no difference in the expression of D2-40 between the more severe and the less severe groups. All other immunohistological parameters showed significantly higher values in the more severe group (p ≤ 0.002). The expression of VEGF-D, MMP-9 and mTOR in LAM cells was associated with the density of both cysts and nodules. The density of cysts and nodules as well as the expression of MMP-9 and VEGF-D were associated with the impairment of PFT parameters. CONCLUSIONS: Severe LAM represents an active phase of the disease with high expression of VEGF-D, mTOR, and MMP-9, as well as LAM cell infiltration. Our findings suggest that the tissue expression levels of VEGF-D and MMP-9 are important parameters associated with the loss of pulmonary function and could be considered as potential severity markers in open lung biopsies of LAM patients.

Evaluation of the extent of pulmonary cysts and their association with functional variables and serum markers in lymphangioleiomyomatosis (LAM).

PURPOSE: Although computed tomography (CT) has been used previously to assess disease severity in lymphangioleiomyomatosis (LAM), the associations between the extent of pulmonary cysts on CT and six-minute walk test (6MWT), matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF-D) are not well established. We performed a cross-sectional study to quantify the extent of pulmonary cysts in CT and to establish their correlations with pulmonary function tests (PFTs), 6MWT results, including a composite index (desaturation-distance ratio, DDR), and levels of VEGF-D and MMPs in LAM. METHODS: Twenty-three LAM patients underwent CT scanning to automatically quantify the extent of pulmonary cysts and performed PFTs and 6MWT. Serum levels of MMP-2, MMP-9, and VEGF-D were also measured. RESULTS: The severity of pulmonary cystic involvement was mild (the extent of cysts was 6.8 %) and correlated best with FEV1/FVC (r = -0.84), residual volume (r = 0.66), DLCO (r = -0.82), the DDR index (r = 0.77), and desaturation during the 6MWT (r = -0.81). There was a weak correlation with VEGF-D (r = 0.45), but no association was found with MMP-2 and MMP-9. CONCLUSIONS: The severity of pulmonary cystic involvement was mild in this sample of LAM patients and correlated best with airway obstruction, air trapping, reduced DLCO, the DDR index, and desaturation during the 6MWT. Serum VEGF-D cannot be completely defined as a valuable marker of disease severity and there may be a mechanism independent of MMPs to explain the formation of pulmonary cysts.

Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare disease that promotes pulmonary cystic destruction and impairs pulmonary function. We aim to describe features and clinical course of LAM patients from Brazil. METHODS: We described the clinical and functional features, performance in six minute walk test (6MWT), management details, survival and clinical course of 84 LAM patients followed in a Brazilian reference centre. RESULTS: All subjects were women, the average age at onset of symptoms was 38 years, and the average at diagnosis was 42 years. The major symptoms during the course of the disease were dyspnoea and pneumothorax. The patients experienced impaired quality of life, with worse scores in the physical and emotional domains. The most common abnormalities in pulmonary function tests were an obstructive pattern and reduced diffusion capacity, whereas a quarter of the patients had normal spirometric results. In the 6MWT, although patients had preserved exercise capacity, more than half of the patients had significant desaturation. Hormonal blockage and doxycycline were the most common treatment modalities employed in our patients. The survival probability from diagnosis was 90% at 5 years, whereas the mean annual rate of decline in FEV1 was 60 ± 78 mL. CONCLUSIONS: Clinical and functional features of the LAM patients from our centre are similar to those from other countries. Our sample showed preserved exercise capacity, with desaturation in the 6MWT, and impaired quality of life. Survival was similar, whereas the annual rate of decline of FEV1 was slightly lower than in recent studies.

Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response.

OBJECTIVE: To assess blockade of matrix metalloproteinase (MMP)-2 and MMP-9, as well as the variation in FEV1, in patients with lymphangioleiomyomatosis (LAM) treated with doxycycline (a known MMP inhibitor) for 12 months. METHODS: An open-label, single-arm, interventional clinical trial in which LAM patients received doxycycline (100 mg/day) for 12 months. Patients underwent full pulmonary function testing, a six-minute walk test, and quality of life assessment, as well as blood and urine sampling for quantification of MMP-2, MMP-9, and VEGF-D levels-at baseline, as well as at 6 and 12 months after the initiation of doxycycline. RESULTS: Thirty-one LAM patients received doxycycline for 12 months. Although there was effective blockade of urinary MMP-9 and serum MMP-2 after treatment, there were no significant differences between pre- and post-doxycycline serum levels of MMP-9 and VEGF-D. On the basis of their response to doxycycline (as determined by the variation in FEV1), the patients were divided into two groups: the doxycycline-responder (doxy-R) group (n = 13); and the doxycycline-nonresponder (doxy-NR) group (n = 18). The patients with mild spirometric abnormalities responded better to doxycycline. The most common side effects were mild epigastric pain, nausea, and diarrhea. CONCLUSIONS: In patients with LAM, doxycycline treatment results in effective MMP blockade, as well as in improved lung function and quality of life in those with less severe disease. However, these benefits do not seem to be related to the MMP blockade, raising the hypothesis that there is a different mechanism of action. (Brazilian Registry of Clinical Trials - ReBEC; identification number RBR-6g8yz9 [http://www.ensaiosclinicos.gov.br]).

A pilot study assessing the effect of bronchodilator on dynamic hyperinflation in LAM.

INTRODUCTION: Positive responses to bronchodilators (BDs) on spirometry can be found in up to 30% of patients with lymphangioleiomyomatosis (LAM). However, no previous studies have investigated the impact of BDs on exercise outcomes, including dynamic hyperinflation (DH). METHODS: A randomised, double-blind, placebo-controlled, crossover trial was conducted on 38 patients with LAM, comparing inhaled placebo versus salbutamol. Pulmonary function tests and a cycle endurance test at 75% of the maximal work capacity, with evaluation of DH by serial measurement of inspiratory capacity (IC), which was the primary endpoint, were performed after each intervention. RESULTS: Although salbutamol produced a slight improvement in airway obstruction, compared with placebo, there was no significant variation in resting IC or air trapping. A total of 18% of the patients met the criteria for a positive response to BD. During submaximal exercise, BD did not reduce DH or dyspnoea nor did it improve exercise tolerance in the entire population. In addition, BD produced only slight improvement in FEV1 and air trapping in patients who had DH during incremental cardiopulmonary exercise testing, without the beneficial effects on exercise outcomes. CONCLUSIONS: Although salbutamol produced a slight improvement in airway obstruction, it did not lead to a reduction in DH or increase in exercise tolerance in patients with LAM. CLINICAL TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC); www.ensaiosclinicos.gov.br; registration number: RBR-49sk2j.

Highlights of the Brazilian Thoracic Association guidelines for interstitial lung diseases.

Interstitial lung diseases (ILDs) are heterogeneous disorders, involving a large number of conditions, the approach to which continues to pose an enormous challenge for pulmonologists. The 2012 Brazilian Thoracic Association ILD Guidelines were established in order to provide Brazilian pulmonologists with an instrument that can facilitate the management of patients with ILDs, standardizing the criteria used for the diagnosis of different conditions and offering guidance on the best treatment in various situations. The objective of this article was to briefly describe the highlights of those guidelines.

Doxycycline use in patients with lymphangioleiomyomatosis: safety and efficacy in metalloproteinase blockade.

OBJECTIVE: Lymphangioleiomyomatosis (LAM) is characterized by lung cysts, whose development is associated with matrix metalloproteinase (MMP) hyperactivity, principally that of MMP-2 and MMP-9. Our objective was to compare LAM patients and controls in terms of the levels of these MMPs, as well as to determine the safety and efficacy of treatment with doxycycline, a potent MMP inhibitor. METHODS: Prospective clinical study involving female LAM patients who received doxycycline (100 mg/day) for six months. Urine and blood samples were collected for the quantification of MMP-2 and MMP-9 before and after the treatment period. Samples from 10 healthy women were also collected. RESULTS: Of the 41 LAM patients who started the treatment, 34 completed the protocol. Serum and urinary MMP-9 levels were significantly lower in the controls than in the LAM patients (p < 0.0001). Comparing pre- and post-treatment values, we found that the median level of MMP-9 in serum decreased from 919 ng/mL to 871 ng/mL (p = 0.05), whereas that of MMP-9 in urine decreased from 11,558 pg/mL to 7,315 pg/mL (p = 0.10). After treatment, the median level of MMP-2 in serum was significantly lower (p = 0.04) and urinary MMP-2 levels were undetectable. Nausea, diarrhea, and epigastric pain were the most prevalent adverse affects and were often self-limiting. There was only one case in which the patient discontinued the treatment because of side effects. CONCLUSIONS: We have demonstrated, for the first time, a decrease in serum and urine levels of MMPs in LAM patients treated with doxycycline, which proved to be a safe medication, with mild and well-tolerated side effects.

Evolution of pulmonary function after treatment with goserelin in patients with lymphangioleiomyomatosis.

In the atypical smooth muscle cells that are characteristic of lymphangioleiomyomatosis (LAM), there are estrogen and progesterone receptors. Therefore, anti-hormonal therapy, despite having produced controversial results, can be considered a treatment option. The objective of this retrospective study was to evaluate hormonal and spirometric data for nine women with LAM after one year of treatment with goserelin. The mean increase in FEV1 and FVC was 80 mL and 130 mL, respectively. There was effective blockage of the hormonal axis. It is still not possible to exclude a potential beneficial effect of the use of gonadotropin-releasing hormone analogues in LAM patients, which underscores the need for randomized trials.

Desaturation - distance ratio: a new concept for a functional assessment of interstitial lung diseases.

INTRODUCTION: The functional evaluation has become increasingly important in the understanding and management of patients with interstitial lung diseases. The cardiopulmonary exercise test and the six-minute walk test (6MWT), through their isolated variables, have been used to do this evaluation, with some limitations. OBJECTIVES: We proposed a new composite index (desaturation distance ratio using continuous peripheral oxygen saturation (SpO2) and the distance walked as a more reliable tool for doing a functional evaluation of these patients. METHODS: 6MWT was performed by interstitial lung diseases patients and controls. Analyzed parameters were walked distance and desaturation area (DAO2), obtained by taking the difference between maximal SpO2 possible (100%) and patient's SpO2 every 2 seconds. desaturation distance ratio was calculated using the ratio between DAO2 and distance walked. RESULTS: Forty-nine interstitial lung diseases patients and 11 control subjects completed the protocol. The mean (SD) age was 60 (12) years and 65 (9) years, respectively (p:NS). Data obtained from 6MWT showed a significant statistical difference between interstitial lung diseases patients and controls: mean walked distance (430 and 602 meters, respectively); SpO2 minimal maintained at least 10 seconds - SpO2 min (85% and 94%, respectively), and median desaturation distance ratio (10 and 2.5, respectively). A correlation analysis, considering interstitial lung diseases patients, revealed the best correlation between desaturation distance ratio and DLco (r= - 0.72; p<0.001), being the correlation between SpO2 min and DLco of 0.61 (p<0.001) and among walked distance and DLco of 0.58 (p<0.05). CONCLUSION: Desaturation distance ratio is a promising concept and a more reliable physiologic tool to assess pulmonary diseases characterized by involvement of the alveolar-capillary membrane, such as interstitial lung diseases.

Doxiciclina em pacientes com linfangioleiomiomatose: biomarcadores e resposta funcional pulmonar / Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response

OBJETIVO: Avaliar o bloqueio da metaloproteinase da matriz (MMP)-2 e da MMP-9 e a variação do VEF1 em pacientes com linfangioleiomiomatose (LAM) após o uso de doxiciclina, um conhecido inibidor de MMP, durante 12 meses. MÉTODOS: Ensaio clínico aberto de braço único no qual as pacientes com diagnóstico de LAM receberam doxiciclina (100 mg/dia) durante 12 meses. Elas foram submetidas a prova de função pulmonar completa, teste de caminhada de seis minutos, avaliação da qualidade de vida e coleta de amostras séricas e urinárias para dosagem de MMP-2, MMP-9 e VEGF-D antes do início do tratamento com doxiciclina e após 6 e 12 meses de tratamento. RESULTADOS: Trinta e uma pacientes com LAM receberam doxiciclina durante 12 meses. Embora tenha havido um bloqueio efetivo da MMP-9 urinária e da MMP-2 sérica após o tratamento, os níveis séricos de MMP-9 e VEGF-D permaneceram estáveis. Com base na resposta à doxiciclina (determinada pela variação do VEF1), as pacientes foram divididas em dois grupos: respondedoras (doxi-R; n = 13) e não respondedoras (doxi-NR; n = 18). As pacientes com alterações espirométricas leves apresentaram melhor resposta à doxiciclina. Os efeitos colaterais mais comuns foram epigastralgia, náusea e diarreia, todos de leve intensidade. CONCLUSÕES: Em pacientes com LAM, o tratamento com doxiciclina resulta em um bloqueio eficaz das MMP, além de melhorar a função pulmonar e a qualidade de vida daqueles com doença menos grave. No entanto, esses benefícios não parecem estar relacionados ao bloqueio das MMP, o que sugere um mecanismo de ação diferente. (Registro Brasileiro de Ensaios Clínicos - ReBEC; número de identificação RBR-6g8yz9 [http://www.ensaiosclinicos.gov.br]).

OBJECTIVE: To assess blockade of matrix metalloproteinase (MMP)-2 and MMP-9, as well as the variation in FEV1, in patients with lymphangioleiomyomatosis (LAM) treated with doxycycline (a known MMP inhibitor) for 12 months. METHODS: An open-label, single-arm, interventional clinical trial in which LAM patients received doxycycline (100 mg/day) for 12 months. Patients underwent full pulmonary function testing, a six-minute walk test, and quality of life assessment, as well as blood and urine sampling for quantification of MMP-2, MMP-9, and VEGF-D levels-at baseline, as well as at 6 and 12 months after the initiation of doxycycline. RESULTS: Thirty-one LAM patients received doxycycline for 12 months. Although there was effective blockade of urinary MMP-9 and serum MMP-2 after treatment, there were no significant differences between pre- and post-doxycycline serum levels of MMP-9 and VEGF-D. On the basis of their response to doxycycline (as determined by the variation in FEV1), the patients were divided into two groups: the doxycycline-responder (doxy-R) group (n = 13); and the doxycycline-nonresponder (doxy-NR) group (n = 18). The patients with mild spirometric abnormalities responded better to doxycycline. The most common side effects were mild epigastric pain, nausea, and diarrhea. CONCLUSIONS: In patients with LAM, doxycycline treatment results in effective MMP blockade, as well as in improved lung function and quality of life in those with less severe disease. However, these benefits do not seem to be related to the MMP blockade, raising the hypothesis that there is a different mechanism of action. (Brazilian Registry of Clinical Trials - ReBEC; identification number RBR-6g8yz9 [http://www.ensaiosclinicos.gov.br]).

Destaques das diretrizes de doenças pulmonares intersticiais da Sociedade Brasileira de Pneumologia e Tisiologia / Highlights of the Brazilian Thoracic Association guidelines for interstitial lung diseases

As doenças pulmonares intersticiais (DPIs) são afecções heterogêneas, envolvendo um elevado número de condições, cuja abordagem ainda é um grande desafio para o pneumologista. As Diretrizes de DPIs da Sociedade Brasileira de Pneumologia e Tisiologia, publicadas em 2012, foram estabelecidas com o intuito de fornecer aos pneumologistas brasileiros um instrumento que possa facilitar a abordagem dos pacientes com DPIs, padronizando-se os critérios utilizados para a definição diagnóstica das diferentes condições, além de orientar sobre o melhor tratamento nas diferentes situações. Esse artigo teve como objetivo descrever resumidamente os principais destaques dessas diretrizes.

Interstitial lung diseases (ILDs) are heterogeneous disorders, involving a large number of conditions, the approach to which continues to pose an enormous challenge for pulmonologists. The 2012 Brazilian Thoracic Association ILD Guidelines were established in order to provide Brazilian pulmonologists with an instrument that can facilitate the management of patients with ILDs, standardizing the criteria used for the diagnosis of different conditions and offering guidance on the best treatment in various situations. The objective of this article was to briefly describe the highlights of those guidelines.

Doxiciclina em pacientes com linfangioleiomiomatose: segurança e eficácia no bloqueio de metaloproteinases / Doxycycline use in patients with lymphangioleiomyomatosis: safety and efficacy in metalloproteinase blockade

OBJETIVO: A linfangioleiomiomatose (LAM) é caracterizada pela presença de cistos pulmonares, cuja formação está associada à hiperreatividade de metaloproteinases de matriz (MMP), principalmente MMP-2 e MMP-9. Objetivamos comparar os níveis dessas MMPs entre pacientes com LAM e controles saudáveis, assim como avaliar, nas pacientes com LAM, a segurança e a eficácia do tratamento com doxiciclina, um potente inibidor de MMPs. MÉTODOS: Estudo clínico prospectivo no qual as pacientes com LAM receberam doxiciclina (100 mg/dia) por seis meses, coletando-se amostras de urina e sangue para a dosagem de MMP-2 e MMP-9 antes e ao final do período. Foram ainda obtidas amostras de 10 mulheres saudáveis. RESULTADOS: De 41 pacientes com LAM que iniciaram o tratamento, 34 concluíram o protocolo. Os níveis de MMP-9 sérica e urinária foram significativamente inferiores no grupo controle (p < 0,0001). Comparando-se os valores antes e após o tratamento, a mediana do nível sérico da MMP-9 reduziu de 919 ng/mL para 871 ng/mL (p = 0,05), enquanto a mediana da dosagem urinária de MMP-9 diminui de 11.558 pg/mL para 7.315 pg/mL (p = 0,10). A mediana da MMP-2 sérica apresentou um decréscimo significativo após o tratamento (p = 0,04). Não foram detectados níveis de MMP-2 urinária. Epigastralgia, náuseas e diarreia foram os efeitos adversos mais prevalentes, e geralmente autolimitados. Apenas 1 paciente interrompeu o tratamento devido a efeitos colaterais. CONCLUSÕES: Pela primeira vez, conseguiu-se evidenciar em pacientes com LAM a redução dos níveis séricos e urinários de MMPs após o uso de doxiciclina, que se mostrou uma medicação segura, com efeitos colaterais leves e toleráveis.

OBJECTIVE: Lymphangioleiomyomatosis (LAM) is characterized by lung cysts, whose development is associated with matrix metalloproteinase (MMP) hyperactivity, principally that of MMP-2 and MMP-9. Our objective was to compare LAM patients and controls in terms of the levels of these MMPs, as well as to determine the safety and efficacy of treatment with doxycycline, a potent MMP inhibitor. METHODS: Prospective clinical study involving female LAM patients who received doxycycline (100 mg/day) for six months. Urine and blood samples were collected for the quantification of MMP-2 and MMP-9 before and after the treatment period. Samples from 10 healthy women were also collected. RESULTS:Of the 41 LAM patients who started the treatment, 34 completed the protocol. Serum and urinary MMP-9 levels were significantly lower in the controls than in the LAM patients (p < 0.0001). Comparing pre- and post-treatment values, we found that the median level of MMP-9 in serum decreased from 919 ng/mL to 871 ng/mL (p = 0.05), whereas that of MMP-9 in urine decreased from 11,558 pg/mL to 7,315 pg/mL (p = 0.10). After treatment, the median level of MMP-2 in serum was significantly lower (p = 0.04) and urinary MMP-2 levels were undetectable. Nausea, diarrhea, and epigastric pain were the most prevalent adverse affects and were often self-limiting. There was only one case in which the patient discontinued the treatment because of side effects. CONCLUSIONS: We have demonstrated, for the first time, a decrease in serum and urine levels of MMPs in LAM patients treated with doxycycline, which proved to be a safe medication, with mild and well-tolerated side effects.

Evolução da função pulmonar após tratamento com goserelina em pacientes com linfangioleiomiomatose / Evolution of pulmonary function after treatment with goserelin in patients with lymphangioleiomyomatosis

Nas células musculares lisas atípicas características da linfangioleiomiomatose (LAM) encontram-se receptores de estrogênio e progesterona, de modo que o tratamento anti-hormonal pode ser considerado uma opção, mas ainda com resultados controversos. O objetivo deste trabalho foi avaliar retrospectivamente parâmetros hormonais e espirométricos em nove mulheres com LAM após o tratamento com goserelina por um ano. Houve um aumento médio de 80 mL e 130 mL, respectivamente, em VEF1 e CVF, assim como bloqueio hormonal efetivo. Ainda não se pode excluir um potencial efeito favorável da utilização de análogos de hormônio liberador de gonadotrofina em pacientes com LAM, reforçando a necessidade de ensaios randomizados.

In the atypical smooth muscle cells that are characteristic of lymphangioleiomyomatosis (LAM), there are estrogen and progesterone receptors. Therefore, anti-hormonal therapy, despite having produced controversial results, can be considered a treatment option. The objective of this retrospective study was to evaluate hormonal and spirometric data for nine women with LAM after one year of treatment with goserelin. The mean increase in FEV1 and FVC was 80 mL and 130 mL, respectively. There was effective blockage of the hormonal axis. It is still not possible to exclude a potential beneficial effect of the use of gonadotropin-releasing hormone analogues in LAM patients, which underscores the need for randomized trials.

Desaturation - distance ratio: a new concept for a functional assessment of interstitial lung diseases

INTRODUCTION: The functional evaluation has become increasingly important in the understanding and management of patients with interstitial lung diseases. The cardiopulmonary exercise test and the six-minute walk test (6MWT), through their isolated variables, have been used to do this evaluation, with some limitations. OBJECTIVES: We proposed a new composite index (desaturation distance ratio using continuous peripheral oxygen saturation (SpO2) and the distance walked as a more reliable tool for doing a functional evaluation of these patients. METHODS: 6MWT was performed by interstitial lung diseases patients and controls. Analyzed parameters were walked distance and desaturation area (DAO2), obtained by taking the difference between maximal SpO2 possible (100 percent) and patient's SpO2 every 2 seconds. desaturation distance ratio was calculated using the ratio between DAO2 and distance walked. RESULTS: Forty-nine interstitial lung diseases patients and 11 control subjects completed the protocol. The mean (SD) age was 60 (12) years and 65 (9) years, respectively (p:NS). Data obtained from 6MWT showed a significant statistical difference between interstitial lung diseases patients and controls: mean walked distance (430 and 602 meters, respectively); SpO2 minimal maintained at least 10 seconds - SpO2 min (85 percent and 94 percent, respectively), and median desaturation distance ratio (10 and 2.5, respectively). A correlation analysis, considering interstitial lung diseases patients, revealed the best correlation between desaturation distance ratio and DLco (r= - 0.72; p<0.001), being the correlation between SpO2 min and DLco of 0.61 (p<0.001) and among walked distance and DLco of 0.58 (p<0.05). CONCLUSION: Desaturation distance ratio is a promising concept and a more reliable physiologic tool to assess pulmonary diseases characterized by involvement of the alveolar-capillary membrane, such as interstitial lung diseases.

Avaliação dos efeitos da doxiciclina sobre o bloqueio de metaloproteinases e na evolução funcional das pacientes com linfangioleiomiomatose / Evaluation of treatment with doxycycline over metalloproteinase blockage and functional assessment in patients with lymphangioleiomyomatosis

A Linfangioleiomiomatose (LAM) é uma rara afecção, caracterizada pela substituição do parênquima pulmonar por cistos, resultando em prejuízo na troca gasosa e progressiva piora funcional. A patogênese da formação dos cistos permanece incerta, mas tem sido associada à hiperreatividade de metaloproteinases (MMP), principalmente MMP-2 e -9. Neste estudo foram avaliados os efeitos da doxiciclina, um potente inibidor de MMP, sobre a eficácia no bloqueio dos níveis sérico e urinário das MMP-2 e -9 após 12 meses de tratamento, bem como sobre os parâmetros funcionais das pacientes com LAM. Foi delineado um ensaio clínico prospectivo, não randomizado e não controlado, no qual as pacientes com LAM receberam doxiciclina (100 mg/dia) por 12 meses, realizando avaliações nos meses basal, 6 e 12 mês, através de prova de função pulmonar completa, teste de caminhada de seis minutos (TC6M), questionário de qualidade de vida (SF-36) e coleta de amostras de urina e sangue para dosagem das MMP-2 e -9. No total, 31 pacientes, com idade média (DP) de 43 (8) anos e diagnóstico estabelecido de LAM, receberam doxiciclina durante 12 meses. Após análise, observou-se bloqueio efetivo sobre a MMP-9 urinária, sendo a mediana (IQ) pré-doxiciclina de 10.487 pg/mL (4.565-20.963) e de 4.061 pg/mL (712-9.985) após 12 meses de doxiciclina (p<0,001). A MMP-2 sérica foi igualmente bloqueada, sendo a mediana (IQ) basal de 0 pg/mL (0-833) e de 0 pg/mL (0-179) após 12 meses (p=0,005). Não houve mudança significativa na MMP-9 sérica e os níveis urinários de MMP-2 não foram detectados nas pacientes. Na análise funcional, apesar de ter havido declínio de 70 mL na média do VEF1 das 31 pacientes, após 12 meses de tratamento, observou-se dois grupos distintos funcionalmente e em relação à qualidade de vida. Estes grupos foram obtidos de acordo com a variação do VEF1, sendo o primeiro grupo compreendido por 13 pacientes, em que o VEF1 permaneceu estável ou aumentou (G1), e o segundo com 18...

Lymphangioleiomyomatosis (LAM) is a rare disease, characterized by substitution of lung parenchyma by cysts, resulting in impairment in the gas exchange and progressive functional worsening. The pathogenesis of development of cysts remains uncertain, but has been associated to overexpression of metalloproteinases (MMP), especially MMP-2 and -9. In this study, there have been analyzed the MMP-2 and MMP-9 blockage in the urine and blood of LAM patients, after doxycycline administration during 12 months, as well as on functional and quality of life parameters of LAM patients. A prospective clinical trial, non randomized and uncontrolled, has been designed, in which LAM patients have received doxycycline (100mg/day) for 12 months, and underwent pulmonary function tests, six-minute walk test (6MWT), quality of life assessment and blood and urine samples for MMP-2 e -9 dosage, undergoing evaluation in months basal, 6th and 12th. Overall, 31 patients mean age (SD) 43 (8) with established diagnosis of LAM have received doxycycline for 12 months. After analysis, it was observed an effective blockage over urinary MMP-9 levels, with a pre-doxycycline median (IQ) of 10,487 pg/mL (4,565-20,963), and 4,061 pg/mL (712-9,985) after 12-month doxycycline administration (p<0.001). The serum MMP-2 has been as well blocked with a basal median (IQ) of 0 pg/mL (0-833), and 0 pg/mL (0-179) after 12 months (p=0.005). There was no significant difference in serum MMP-9 levels, and urinary MMP-2 levels were untraceable. During functional parameters analysis, although there was a mean decline of 70 mL in FEV1 in the 31 patients after doxycycline treatment, we noticed two different groups concerning to the assessment of function tests and quality of life. These groups were obtained according to FEV1 variation; the first group comprised 13 patients in which the FEV1 increased or remained stable (G1), and the second group comprised 18 LAM patients in which FEV1 decreased (G2)...