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Fernando J Martinez

Publications and source records attributed to Fernando J Martinez.

At least 37 records · Page 2Linked to original sources
PubMed2006

Idiopathic interstitial pneumonias: usual interstitial pneumonia versus nonspecific interstitial pneumonia.

Diffuse parenchymal lung diseases (DPLDs) are a group of disorders that involve the space between the epithelial and endothelial basement membranes. Recent guidelines for the classification of DPLDs recommended separating patients into several categories, including (1) DPLDs of known cause, (2) granulomatous DPLDs, (3) rare DPLDs with well-defined clinicopathologic features, and (4) the idiopathic interstitial pneumonias (IIPs). The IIPs are further subdivided into categories that include usual interstitial pneumonia (idiopathic pulmonary fibrosis [IPF] if the usual interstitial pneumonia is idiopathic in origin) and nonspecific interstitial pneumonia. In numerous cohorts, IPF has been associated with impaired prognosis compared with nonspecific interstitial pneumonia, except in the setting of markedly impaired physiology at presentation. It is therefore imperative for the health care provider to rapidly assess the likelihood of a patient having IPF. The diagnostic approach has been refined over the past several years, with much clearer recommendations addressing the optimal clinical, radiologic, and laboratory assessments of patients with IIPs. Similarly, therapeutic interventions have rapidly evolved, with less emphasis on standard immunosuppression and increasing focus on interventions targeting fibroproliferation. Numerous therapeutic trials have recently been completed, are ongoing, or are soon to begin patient recruitment. A multicenter, National Institutes of Health-funded clinical research network has been convened to target novel therapeutic approaches in well-designed controlled trials. The next few years will be an exciting time in the evaluation and treatment of DPLDs as increasing clinically relevant biological information is translated to novel diagnostic and therapeutic approaches.

Diagnosis, Differential↗
PubMed2006

Pulmonary function testing in idiopathic interstitial pneumonias.

Diffuse parenchymal lung diseases are a group of disorders that involve the space between the epithelial and endothelial basement membranes and are generally segregated into four major categories. These include the idiopathic interstitial pneumonias, which are further categorized into seven clinical/radiologic/pathologic subsets. These disorders generally share a common pattern of physiologic abnormality characterized by a restrictive ventilatory defect and reduced diffusing capacity (DLCO). Pulmonary function testing is often used and recommended in their assessment and management. The potential clinical application of physiologic testing includes to aid in diagnosis, although its value in differential diagnosis is limited. Pulmonary function testing also aids in establishing disease severity and in defining prognosis. In nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis, severely decreased DLCO has proven valuable in this regard. Similarly, exertional desaturation to less than 88% at baseline testing and a decrease in FVC (greater than 10%) over the course of short-term follow-up identify patients at particular risk of mortality. Finally, physiologic testing, especially spirometry and DLCO, have demonstrated value in monitoring response to therapy and identifying disease progression.

Diagnosis, Differential↗
PubMed2006

Role of infection and antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease.

Over the past several years, the significance of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in patients with chronic airflow obstruction has become increasingly apparent due to the impact these episodes have on the natural history of disease. It is now known that frequent AECOPD can adversely affect a patient's health-related quality of life and short- and long-term pulmonary function. The economic burden of these episodes is also substantial. AECOPDs represent a local and systemic inflammatory response to both infectious and noninfectious stimuli, but the majority of episodes are likely related to bacterial or viral pathogens. Patients with purulent sputum and multiple symptoms are the most likely to benefit from treatment with antibiotics. Antibiotic choice should be tailored to the individual patient, taking into account the severity of the episode and host factors which might increase the likelihood of treatment failure. Current evidence suggests that therapeutic goals not only include resolution of the acute episode, but also prolonging the time to the next event. In the future, preventing exacerbations will likely become increasingly accepted as an additional therapeutic goal in chronic obstructive pulmonary disease patients.

Anti-Infective Agents↗
PubMed2006

Obligatory role for interleukin-13 in obstructive lesion development in airway allografts.

The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13Ralpha1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3(+) T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13(-/-) recipients. Transforming growth factor-beta1 expression was significantly decreased in tracheal allografts into IL-13(-/-) recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex-perimental BO.

Adult↗
PubMed2005

Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10).

RATIONALE: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. OBJECTIVE: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs. METHODS: We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production. RESULTS: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype. CONCLUSIONS: The results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.

Actins↗
PubMed2005

The clinical course of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Prospective data defining the clinical course in idiopathic pulmonary fibrosis (IPF) are sparse. OBJECTIVE: To analyze the clinical course of patients with mild to moderate IPF. DESIGN: Analysis of data from the placebo group of a randomized, controlled trial evaluating interferon-gamma1b. SETTING: Academic and community medical centers. PATIENTS: 168 patients in the placebo group of a trial evaluating interferon-gamma1b. MEASUREMENTS: Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations; and the pace of deterioration and cause of death over a median period of 76 weeks. RESULTS: Physiologic variables changed minimally during the study. However, 23% of patients required hospitalization for a respiratory disorder and 21% died. Idiopathic pulmonary fibrosis was the primary cause of death in 89% of patients who died, and an apparent acute clinical deterioration preceded death in 47% of these patients. LIMITATIONS: The instrument used to define the pace of deterioration and cause of death was applied retrospectively. CONCLUSIONS: Recognition of the common occurrence of acute fatal deterioration in patients with mild to moderate IPF has important implications for monitoring patients and supports early referral for lung transplantation.

Aged↗
PubMed2005

Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-lung transplant recipients.

RATIONALE: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75%)), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. OBJECTIVE: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. METHODS: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. RESULTS: BOS 0-p FEV(1) was associated with higher sensitivity, specificity, and positive predictive value than the FEF(25-75%) criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV(1) in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV(1) in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV(1) criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV(1) were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively). CONCLUSION: The FEV(1) criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF(25-75%) criterion.

Bronchiolitis Obliterans↗
PubMed2005

Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts.

Cell-cell signaling roles for reactive oxygen species (ROS) generated in response to growth factors/cytokines in nonphagocytic cells are not well defined. In this study, we show that fibroblasts isolated from lungs of patients with idiopathic pulmonary fibrosis (IPF) generate extracellular hydrogen peroxide (H2O2) in response to the multifunctional cytokine, transforming growth factor-beta1 (TGF-beta1). In contrast, TGF-beta1 stimulation of small airway epithelial cells (SAECs) does not result in detectable levels of extracellular H2O2. IPF fibroblasts independently stimulated with TGF-beta1 induce loss of viability and death of overlying SAECs when cocultured in a compartmentalized Transwell system. These effects on SAECs are inhibited by the addition of catalase to the coculture system or by the selective enzymatic blockade of H2O2 production by IPF fibroblasts. IPF fibroblasts heterogeneously express alpha-smooth muscle actin stress fibers, a marker of myofibroblast differentiation. Cellular localization of H2O2 by a fluorescent-labeling strategy demonstrated that extracellular secretion of H2O2 is specific to the myofibroblast phenotype. Thus, myofibroblast secretion of H2O2 functions as a diffusible death signal for lung epithelial cells. This novel mechanism for intercellular ROS signaling may be important in physiological/pathophysiological processes characterized by regenerating epithelial cells and activated myofibroblasts.

Catalase↗
PubMed2005

Appropriate outpatient treatment of acute bacterial exacerbations of chronic bronchitis.

Acute exacerbations of chronic bronchitis (AECB), which are characteristic of chronic obstructive pulmonary disease (COPD), contribute to morbidity and decreased quality of life for patients with COPD. A significant proportion of these exacerbations are due to bacterial infections. The Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria provide guidance for choosing the optimal drug at its optimal dose and duration for antimicrobial treatment of AECB due to bacterial infection. Evidence-based guidelines recommend stratifying patients according to risk factors to improve selection of targeted antimicrobial therapy. With increasing rates of resistance to some antimicrobials, resistance is also an important consideration for reducing treatment failures and decreasing the need for further pharmacologic treatment. Fluoroquinolones are recommended as first-line therapy for patients with chronic bronchitis who have risk factors; gatifloxacin, gemifloxacin, and levofloxacin are highly active against commonly encountered pathogens. Safety profiles are an important consideration because adverse events and poor tolerability can reduce patient adherence rates, which in turn can lead to poorer outcomes. Safety profiles also become an important consideration as shorter-course, higher-dose therapies become more prevalent. First-line therapy with a well-tolerated antibiotic that is active against the predominant pathogens, combined with low resistance rates and a convenient once-a-day dosing regimen, may reduce overall costs. Fluoroquinolones exhibit low resistance, good activity levels, and high respiratory penetration, and they are particularly well suited for shorter-course, higher-dose regimens in selected patients. Shorter-course, higher dose regimens, in turn, may be more effective, cost-efficient, and appropriate for controlling the rise of resistance than standard regimens.

Acute Disease↗
PubMed2005

Physician and patient perceptions in COPD: the COPD Resource Network Needs Assessment Survey.

PURPOSE: Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States, has received disproportionately little attention from physicians and institutions. National data are lacking on patient and physician perceptions of and patterns of care for COPD. METHODS: Linked surveys were administered to national samples of patients with COPD, primary care physicians, and pulmonologists to evaluate perceptions of COPD severity and quality of life, attitudes about COPD, health insurance barriers to COPD care, sources of information, and knowledge about COPD diagnosis and treatment. RESULTS: Overall, 1023 patients with COPD and 1051 primary care physicians and pulmonologists responded to the surveys. Despite experiencing significant symptoms and high health care use, the majority of patients were satisfied with their care. Eighty-eight percent of physicians agreed with the statement that COPD is a "self-inflicted" disease, and more than one third were nihilistic about the treatment of patients who continued to smoke. Patients and physicians reported that insurance problems impeded access to therapies. Patients were generally uninformed about COPD; 54% of primary care physicians were aware of any COPD guidelines. Both patient and physician surveys demonstrated continued confusion about the diagnosis of COPD and treatment choices. There was frequent use of regular oral steroids despite demonstrated lack of efficacy and under-use of pulmonary rehabilitation despite proven efficacy. CONCLUSIONS: Patients with COPD have a high prevalence of activity limitations. Although most physicians believed that proper treatment can slow progression, inadequate knowledge and poor adherence to practice guidelines, together with insurance impediments, negatively impact COPD care.

Adult↗
PubMed2005

Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury.

Progressive fibrotic diseases involving diverse organ systems are associated with the persistence of fibroblasts/myofibroblasts in injured tissues. Activation of focal adhesion kinase (FAK) and protein kinase B (PKB/Akt) by transforming growth factor-beta1 mediate stable induction of myofibroblast differentiation and survival. In this report, we demonstrate that transforming growth factor-beta1-induced activation of both PKB/Akt and FAK are dose dependently inhibited by the protein kinase inhibitor, AG1879, in cultured human lung fibroblasts. In a murine model of intratracheal bleomycin-induced lung fibrosis, regions of active fibrogenesis demonstrate elevated expression of PKB/Akt and FAK phosphorylation in vivo, effects that are attenuated in mice receiving daily intraperitoneal injections of AG1879 (bleomycin-AG1879) versus a chemically inactive analog (bleomycin-control). PKB/Akt and FAK phosphorylation are elevated in fibroblasts isolated from lungs of bleomycin-injured mice, effects that are inhibited in bleomycin-AG1879 mice. Accumulation of alpha-smooth muscle actin-expressing myofibroblasts is markedly reduced in lungs of bleomycin-AG1879 mice. The numbers of recruited inflammatory cells were not significantly different between these groups. Bleomycin-AG1879 mice are protected from lung fibrosis as evidenced by histopathology, trichrome staining, and biochemical analysis for collagen. Thus, targeting of prosurvival signaling pathways in fibroblasts/myofibroblasts may provide a novel and effective strategy for anti-fibrotic therapy of treatment-unresponsive fibrotic disorders.

Actins↗
PubMed2005

Acute exacerbation of chronic bronchitis: expanding short-course therapy.

Recent management guidelines for acute exacerbation of chronic bronchitis (AECB) have provided antimicrobial options for different classes of patients according to varying disease severity or risk of treatment failure. In a pivotal, double-blind, double-dummy study comparing azithromycin microspheres (2 g single dose) with the respiratory quinolone levofloxacin (500 mg once daily x 7 days) for the treatment of AECB, the two regimens were equally effective and well tolerated in patients with mild-to-moderate disease (clinical cure rate 93.6% vs. 92.7%, respectively [95% confidence interval (CI) for difference, -3.4, 5.5] and overall bacteriological eradication rate 91.9% vs. 94.4%, respectively (95% CI for difference, -8.8, 3.8). Interestingly, additional post hoc analyses suggest that a single dose of azithromycin also provides comparable clinical efficacy to levofloxacin in patients with a forced expiratory volume in 1 s (FEV1) of less than 70% of the predicted value, a risk factor that would place them in a more severe stratum. These data support azithromycin microspheres as an appropriate option in patients with mild-to-moderate AECB. The potential role of this preparation and other macrolides in patients at higher risk of therapeutic failure requires additional prospective data.

Acute Disease↗
PubMed2005

Surgical therapy for chronic obstructive pulmonary disease.

Many patients with severe chronic obstructive pulmonary disease (COPD) experience incapacitating breathlessness and exercise limitation. Multiple surgical techniques have been utilized to achieve resection of giant, localized bullae with documented short-term benefit in pulmonary function and dyspnea in highly selected patients. The poorest long-term outcome has been noted in those with greater degrees of emphysema in the remaining lung, greater underlying chronic bronchitis, and a bulla occupying less than one third of the hemithorax, particularly if compressed normal lung is not evident. Lung volume reduction surgery (LVRS) in the absence of giant bullae has become more widely accepted in selected patients. Bilateral LVRS procedures appear to result in greater short-term improvement than unilateral LVRS, whereas physiological benefits appear similar with video-assisted thoracoscopy (VATS) or median sternotomy (MS) techniques. Improvement in dyspnea and health status after LVRS has been documented and appears to be better preserved over longer-term follow-up than physiological improvement. Clear direction has been provided in identifying optimal candidates for bilateral LVRS; patients with a postbronchodilator forced expiratory volume in 1 second (FEV (1)) < or = 20% predicted and a diffusing capacity for carbon monoxide (DL (CO)) < or = 20% predicted or homogeneous emphysema exhibit a much higher mortality with LVRS than with medical management. Patients with upper-lobe predominant emphysema and a low postrehabilitation exercise tolerance exhibited a decreased risk of mortality after LVRS. Patients with non-upper lobe predominant emphysema on high-resolution computed tomography (HRCT) and a high postrehabilitation exercise capacity exhibit an increased risk of death after LVRS. Patients with upper lobe predominant emphysema and a high postrehabilitation exercise capacity or patients with non-upper lobe predominant emphysema and a low postrehabilitation exercise capacity do not have a survival advantage or disadvantage, whereas those with upper lobe predominant emphysema treated surgically are more likely to improve their exercise capacity after surgery. Lung transplantation is an option for a more limited number of patients. Consistent short-term spirometric improvement after both single- and double-lung transplant has been documented. Long-term results of lung transplantation are limited by significant complications that impair survival; an approximately 80% 1-year, 50% 5-year, and 35% 10-year survival has been reported. Bronchiolitis obliterans is the most important long-term complication of lung transplantation resulting in decreased pulmonary function. In general, a COPD patient can be considered an appropriate candidate for transplantation when the FEV (1) is below 25% predicted and/or the paCO (2) is > or = 55 mm Hg.

Disease Progression↗
PubMed2005

Is it asthma or COPD? The answer determines proper therapy for chronic airflow obstruction.

Evaluation and diagnosis of obstructive lung disease call for careful history taking to distinguish asthma from chronic obstructive pulmonary disease (COPD). A history of atopy and intermittent, reactive symptoms points toward a diagnosis of asthma, whereas smoking and advanced age are more indicative of COPD. Clinical features such as cough and wheezing, especially in light of patient history, can be suggestive but are not definitive. Spirometry, usually performed in the primary care setting, is the key diagnostic tool that distinguishes patients with asthma from patients with COPD. In this article, the authors outline an approach to differential diagnosis of asthma and COPD that should result in better evaluation, therapy, and quality of life for these patients.

Anti-Inflammatory Agents↗
PubMed2004

Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?

Current guidelines recommend that the clinician, radiologist, and pathologist work together to establish a diagnosis of idiopathic interstitial pneumonia. Three clinicians, two radiologists, and two pathologists reviewed 58 consecutive cases of suspected idiopathic interstitial pneumonia. Each participant was provided information in a sequential manner and was asked to record their diagnostic impression and level of confidence at each step. Interobserver agreement improved from the beginning to the end of the review. After the presentation of histopathologic information, radiologists changed their diagnostic impression more often than did clinicians. In general, as more information was provided the confidence level for a given diagnosis improved, and the diagnoses rendered with a high level of confidence were more likely congruent with the final pathologic consensus diagnosis. The final consensus pathologist diagnosis was idiopathic pulmonary fibrosis in 30 cases. Clinicians identified 75% and radiologists identified 48% of these cases before presentation of the histopathologic information. Histopathologic information has the greatest impact on the final diagnosis, especially when the initial clinical/radiographic diagnosis is not idiopathic pulmonary fibrosis. We conclude that dynamic interactions between clinicians, radiologists, and pathologists improve interobserver agreement and diagnostic confidence.

Diagnosis, Differential↗