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King Jr. T.E.,University of California at San Francisco | Pardo A.,National Autonomous University of Mexico | Selman M.,Instituto Nacional Of Enfermedades Respiratorias
The Lancet | Year: 2011

Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis. © 2011 Elsevier Ltd.


Selman M.,Instituto Nacional Of Enfermedades Respiratorias | Pardo A.,National Autonomous University of Mexico | King Jr. T.E.,University of California at San Francisco
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Hypersensitivity pneumonitis (HP) is a complex syndrome resulting from repeated exposure to a variety of organic particles. HP may present as acute, subacute, or chronic clinical forms but with frequent overlap of these various forms. An intriguing question is why only few of the exposed individuals develop the disease. According to a two-hit model, antigen exposure associated with genetic or environmental promoting factors provokes an immunopathological response. This response is mediated by immune complexes in the acute form and by Th1 and likely Th17 T cells in subacute/chronic cases. Pathologically, HP is characterized by a bronchiolocentric granulomatous lymphocytic alveolitis, which evolves to fibrosis in chronic advanced cases. On high-resolution computed tomography scan, ground-glass and poorly defined nodules, with patchy areas of air trapping, are seen in acute/ subacute cases, whereas reticular opacities, volume loss, and traction bronchiectasis superimposed on subacute changes are observed in chronic cases. Importantly, subacute and chronic HP may mimic several interstitial lung diseases, including nonspecific interstitial pneumonia and usual interstitial pneumonia, making diagnosis extremely difficult. Thus, the diagnosis of HP requires a high index of suspicion and should be considered in any patient presenting with clinical evidence of interstitial lung disease. The definitive diagnosis requires exposure to known antigen, and the assemblage of clinical, radiologic, laboratory, and pathologic findings. Early diagnosis and avoidance of further exposure are keys in management of the disease. Corticosteroids are generally used, although their long-term efficacy has not been proved in prospective clinical trials. Lung transplantation should be recommended in cases of progressive end-stage illness. Copyright © 2012 by the American Thoracic Society.


Richeldi L.,National Health Research Institute | Du Bois R.M.,Imperial College London | Raghu G.,University of Washington | Azuma A.,Nippon Medical School | And 19 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. Copyright © 2014 Massachusetts Medical Society.


Perez-Padilla R.,Instituto Nacional Of Enfermedades Respiratorias | Schilmann A.,Instituto Nacional Of Salud Publica | Riojas-Rodriguez H.,Instituto Nacional Of Salud Publica
International Journal of Tuberculosis and Lung Disease | Year: 2010

Domestic pollution is relevant to health because people spend most of their time indoors. One half of the world's population is exposed to high concentrations of solid fuel smoke (biomass and coal) that are produced by inefficient open fires, mainly in the rural areas of developing countries. Concentrations of particulate matter in kitchens increase to the range of milligrams per cubic meter during cooking. Solid fuel smoke possesses the majority of the toxins found in tobacco smoke and has also been associated with a variety of diseases, such as chronic obstructive pulmonary disease in women, acute respiratory infection in children and lung cancer in women (if exposed to coal smoke). Other tobacco smoke-associated diseases, such as tuberculosis, asthma, respiratory tract cancer and interstitial lung diseases, may also be associated with solid fuel smoke inhalation, but evidence is limited. As the desirable change to clean fuels is unlikely, efforts have been made to use efficient, vented wood or coal stoves, with varied success due to inconsistent acceptance by the community. © 2010 The Union.


Burney P.,Imperial College London | Jarvis D.,Imperial College London | Perez-Padilla R.,Instituto Nacional Of Enfermedades Respiratorias
International Journal of Tuberculosis and Lung Disease | Year: 2015

With an aging global population, chronic respiratory diseases are becoming a more prominent cause of death and disability. Age-standardised death rates from chronic obstructive pulmonary disease (COPD) are highest in low-income regions of the world, particularly South Asia and sub-Saharan Africa, although airflow obstruction is relatively uncommon in these areas. Airflow obstruction is, by contrast, more common in regions with a high prevalence of cigarette smoking. COPD mortality is much more closely related to the prevalence of a low forced vital capacity which is, in turn, associated with poverty. Mortality from asthma is less common than mortality from COPD, but it is also relatively more common in poorer areas, particularly Oceania, South and South-East Asia, the Middle East and Africa. Again this contrasts with the asthma prevalence among adults, which is highest in highincome regions. In high-income areas, mortality due to asthma, which is predominantly an adult problem, has fallen substantially in recent decades with the spread of new guidelines for treatment that emphasise the use of inhaled steroids to control the disease. Although mortality rates have been falling, the prevalence of atopy has been increasing between generations in Western Europe. Changes in the prevalence of wheeze among adults has been more varied and may have been influenced by the reduction in smoking and the increase in the use of inhaled steroids. © 2015 The Union.


Bazan-Perkins B.,Instituto Nacional Of Enfermedades Respiratorias
Journal of Muscle Research and Cell Motility | Year: 2012

Ca2+ and cGMP have opposite roles in many physiological processes likely due to a complex negative feedback regulation between them. Examples of opposite functions induced by Ca2+ and cGMP are smooth muscle contraction and relaxation, respectively. A main Ca2+ storage involved in contraction is sarcoplasmic reticulum (SR); nevertheless, the role of cGMP in the regulation of SR-Ca2+ has not been completely understood. To evaluate this role, intracellular Ca2+ concentration ([Ca2+]i) was determinated by a ratiometric method in isolated myocytes from bovine trachea incubated with Fura-2/AM. The release of Ca 2+ from SR induced by caffeine was transient, whereas caffeine withdrawal was followed by a [Ca2+]i undershoot. Caffeine-induced Ca2+ transient peak and [Ca2+]i undershoot after caffeine were reproducible in the same cell. Dibutyryl cGMP (db-cGMP) blocked the [Ca2+]i undershoot and reduced the subsequent caffeine peak (SR-Ca2+ loading). Both, the opening of SR channels with ryanodine (10 μM) and the blockade of SR-Ca2+ ATPase with cyclopiazonic acid inhibited the [Ca2+]i undershoot as well as the SR-Ca2+ loading. The addition of db-cGMP to ryanodine (10 μM) incubated cells partially restored the SR-Ca2+ loading. Cyclic GMP enhanced [Ca 2+]i undershoot induced by the blockade of ryanodine channels with 50 μM ryanodine. In conclusion, the reduction of SR-Ca2+ content in airway smooth muscle induced by cGMP can be explained by the combination of SR-Ca2+ loading and the simultaneous release of SR-Ca2+. The reduction of SR-Ca2+ content induced by cGMP might be a putative mechanism limiting releasable Ca2+ in response to a particular stimulus. © 2011 Springer Science+Business Media B.V.


Ramirez-Venegas A.,Instituto Nacional Of Enfermedades Respiratorias | Sansores R.H.,Instituto Nacional Of Enfermedades Respiratorias | Quintana-Carrillo R.H.,Instituto Nacional Of Enfermedades Respiratorias | Velazquez-Uncal M.,Instituto Nacional Of Enfermedades Respiratorias | And 4 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: Biomass exposure is an important risk factor for chronic obstructive pulmonary disease (COPD). However, the time-course behavior of FEV1 in subjects exposed to biomass is unknown. Objectives: We undertook this study to determine the FEV1 rate decline in subjects exposed to biomass. Methods: Pulmonary function was assessed every year in a Mexican cohort of patients with COPD associated with biomass or tobacco during a 15-year follow-up period. Measurements and Main Results: The mean rate of decline was significantly lower for the biomass exposure COPD group (BE-COPD) than for the tobacco smoke COPD group (TS-COPD) (23 vs. 42 ml, respectively; P < 0.01). Of the TS-COPD group, 11% were rapid decliners, whereas only one rapid decliner was found in the BE-COPD group; 69 and 21% of smokers versus 17 and 83% of the BE-COPD group were slow decliners and sustainers, respectively. A higher FEV1both as % predicted and milliliters was a predictive factor for decline for BE-COPD and TS-COPD, whereas reversibility to bronchodilator was a predictive factor for both groups when adjusted by FEV1% predicted and only for the TS-COPD group when adjusted by milliliters. Conclusions: In the biomass exposure COPD group the rate of FEV1 decline is slower and shows a more homogeneous rate of decline over time in comparison with smokers. The rapid rate of FEV1decline is a rare feature of biomass-induced airflow limitation. Copyright © 2014 by the American Thoracic Society.


Selman M.,Instituto Nacional Of Enfermedades Respiratorias | Buendia-Roldan I.,Instituto Nacional Of Enfermedades Respiratorias
Seminars in Respiratory and Critical Care Medicine | Year: 2012

Hypersensitivity pneumonitis (HP) is an inflammatory interstitial lung disease caused by a wide variety of organic particles and certain small-molecular weight chemical compounds that provoke an exaggerated immune response in susceptible individuals. The clinical manifestations are heterogeneous and have been classically described as acute, subacute and chronic. The chronic form has an insidious onset over a period of months or years, with progressive dyspnea and often evolves to fibrosis. The pathology is characterized by a bronchiolocentric interstitial mononuclear cell infiltration, nonnecrotizing poorly formed granulomas, cellular pneumonitis and variable degrees of fibrosis. However, morphological diagnosis of HP is complicated because the subacute/chronic forms may be difficult to distinguish from idiopathic pulmonary fibrosis/usual interstitial pneumonia and nonspecific interstitial pneumonia. In general, diagnosis of HP represents a challenge for clinicians that need to weigh a constellation of clinical, laboratory, radiographic and (when available) pathological evidence for each patient to assess the certainty of the diagnosis. The cornerstone of therapy is antigen avoidance. Although clinical trials are scanty, corticosteroids are usually indicated based upon expert opinion. In this review we summarize the current evidence regarding the diagnostic criteria and therapeutic strategies as well as the immunopathological mechanisms putatively implicated in the development of the disease. © 2012 by Thieme Medical Publishers, Inc.


Ortiz-Quintero B.,Instituto Nacional Of Enfermedades Respiratorias
Cell Proliferation | Year: 2016

The discovery of cell-free microRNAs (miRNAs) in serum, plasma and other body fluids has yielded an invaluable potential source of non-invasive biomarkers for cancer and other non-malignant diseases. miRNAs in the blood and other body fluids are highly stable in biological samples and are resistant to environmental conditions, such as freezing, thawing or enzymatic degradation, which makes them convenient as potential biomarkers. In addition, they are more easily sampled than tissue miRNAs. Altered levels of cell-free miRNAs have been found in every type of cancer analysed, and increasing evidence indicates that they may participate in carcinogenesis by acting as cell-to-cell signalling molecules. This review summarizes the biological characteristics and mechanisms of release of cell-free miRNAs that make them promising candidates as non-invasive biomarkers of cancer. © 2016 John Wiley & Sons Ltd.


One of the main characteristics of the vasculitis associated with antineutrophil cytoplasm autoantibodies (AASV) is the absence of immune complex deposition in biopsies of affected tissues as well as a lack of complement depletion. However, in early stages of disease induced in animal models, it has been observed that the complement system may be involved in the generation of these diseases. There are various animal models which have been developed with the aim of knowing which are the pathogenic mechanisms in granulomatosis with polyangiitis (Wegener) (GPA) and microscopic polyangiitis (MPA), the latter being explained using these approaches in a more satisfactory manner, as there is lack of a model which reproduces the changes leading to a granulomatous vasculitis associated with antibodies against proteinase-3, as in GPA. This short review presents recent evidence of the presence of complement in biopsies of patients with AASV and the most recent animal models, which show the participation of complement in their etiology. © 2011 Elsevier España, S.L.

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