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ASPEN trial participant characteristics highlight the heterogeneity of non-cystic fibrosis bronchiectasis and global variations in clinical practice patterns https://bit.ly/447XeP0.
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BACKGROUND: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. METHODS: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 µg/dL (<10.7 µmol/L). RESULTS: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 µg/dL serum iron (95 % CI, +26.7-42.1 µg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 µg/dL serum iron (95 % CI, +13.5-30.8 µg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 µg/dL serum iron (95 % CI, +33.3-58.8 µg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). CONCLUSIONS: ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).
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OBJECTIVE: To provide interim advice and considerations to the CF Community around CF nutrition in the current era. METHODS: The Cystic Fibrosis (CF) Foundation organized a multidisciplinary committee to develop a Nutrition Position Paper based on the rapidly changing nutrition landscape in CF, due in part to widespread use of cystic fibrosis transmembrane regulator highly effective modulator therapy (HEMT). Four workgroups were formed: Weight Management, Eating Behavior/Food Insecurity, Salt Homeostasis and Pancreatic Enzyme use. Each workgroup conducted their own focused review of the literature. RESULTS: The committee summarized current understanding of issues pertaining to the four workgroup topics and provided 6 key take-aways around CF Nutrition in the new era. CONCLUSION: People with CF (pwCF) are living longer, particularly with the advent of HEMT. The traditional high fat, high calorie CF diet may have negative nutritional and cardiovascular consequences as pwCF age. Individuals with CF may have poor diet quality, food insecurity, distorted body image, and an higher incidence of eating disorders. An increase in overweight and obesity may lead to new considerations for nutritional management, given potential effects of overnutrition on pulmonary and cardiometabolic parameters.
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Fibrosis Quística , Terapia Nutricional , Humanos , Fibrosis Quística/epidemiología , Fibrosis Quística/terapia , Estado Nutricional , Ingestión de Energía , ObesidadRESUMEN
BACKGROUND: Peripherally inserted central catheters (PICCs) are used commonly to administer antibiotics to people with cystic fibrosis (CF), but their use can be complicated by venous thrombosis and catheter occlusion. RESEARCH QUESTION: Which participant-, catheter-, and catheter management-level attributes are associated with increased risk of complications of PICCs among people with CF? STUDY DESIGN AND METHODS: This was a prospective observational study of adults and children with CF who received PICCs at 10 CF care centers in the United States. The primary end point was defined as occlusion of the catheter resulting in unplanned removal, symptomatic venous thrombosis in the extremity containing the catheter, or both. Three categories of composite secondary outcomes were identified: difficult line placement, local soft tissue or skin reactions, and catheter malfunction. Data specific to the participant, catheter placement, and catheter management were collected in a centralized database. Risk factors for primary and secondary outcomes were analyzed by multivariate logistic regression. RESULTS: Between June 2018 and July 2021, 157 adults and 103 children older than 6 years with CF had 375 PICCs placed. Patients underwent 4,828 catheter-days of observation. Of the 375 PICCs, 334 (89%) were ≤ 4.5 F, 342 (91%) were single lumen, and 366 (98%) were placed using ultrasound guidance. The primary outcome occurred in 15 PICCs for an event rate of 3.11 per 1,000 catheter-days. No cases of catheter-related bloodstream infection occurred. Other secondary outcomes developed in 147 of 375 catheters (39%). Despite evidence of practice variation, no risk factors for the primary outcome and few risk factors for secondary outcomes were identified. INTERPRETATION: This study affirmed the safety of contemporary approaches to inserting and using PICCs in people with CF. Given the low rate of complications in this study, observations may reflect a widespread shift to selecting smaller-diameter PICCs and using ultrasound to guide their placement.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Cateterismo Periférico , Catéteres Venosos Centrales , Fibrosis Quística , Trombosis de la Vena , Adulto , Niño , Humanos , Estudios Prospectivos , Cateterismo Venoso Central/efectos adversos , Cateterismo Venoso Central/métodos , Fibrosis Quística/complicaciones , Fibrosis Quística/terapia , Estudios Retrospectivos , Cateterismo Periférico/efectos adversos , Trombosis de la Vena/etiología , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/etiología , Catéteres de PermanenciaRESUMEN
Cystic fibrosis (CF) is an inherited multisystemic disease that can cause progressive bronchiectasis, pancreatic endocrine and exocrine insufficiency, distal intestinal obstruction syndrome, liver dysfunction, and other disorders. Traditional therapies focused on the treatment or prevention of damage to each organ system with incremental modalities such as nebulized medications for the lungs, insulin for diabetes, and supplementation with pancreatic enzymes. However, the advent of highly effective modulator therapies that target specific cystic fibrosis transmembrane conductance regulator protein malformations resulting from individual genetic mutations has transformed the lives and prognosis for persons with CF.
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Fibrosis Quística , Diabetes Mellitus , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Pronóstico , Mutación , Aminofenoles/uso terapéuticoRESUMEN
Stroke patients with autonomic dysfunction are more likely to develop cardiac problems, which have been linked to lower functional outcomes and increased mortality. In this study, heart rate variability (HRV) detection paired with the Clinical Feature Scale will be utilized to elucidate the immediate impact of manual acupuncture on autonomic dysfunction of varying severity in the convalescence stroke phase. This is a randomized, single-blind, controlled clinical trial approach. At a ratio of 1:1, 60 appropriate patients will be randomly randomized into either the experimental or control group. On the basis of symptomatic treatment drugs, the experimental group will additionally undertake acupuncture therapy 3 times a week for 4 weeks, for a total of 12 times. Primary outcomes include 24-hour HRV and 60-minute HRV detection at week 4 compared with baseline. The secondary outcome is the score of clinical feature scale at week 4 compared with the baseline. Adverse events and safety indices will be recorded throughout the experiment. The SPSS V.25.0 statistical program was applied for analysis, and measurement data were expressed as meanâ ±â SD.
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Disautonomías Primarias , Accidente Cerebrovascular , Humanos , Frecuencia Cardíaca/fisiología , Método Simple Ciego , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/diagnóstico , Vías AutónomasRESUMEN
OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin. METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI. RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI. CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.
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Lesión Renal Aguda , Fibrosis Quística , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Antibacterianos/efectos adversos , Colistina/análogos & derivados , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Combinación Piperacilina y Tazobactam/uso terapéutico , Estudios Retrospectivos , Tobramicina/efectos adversos , Vancomicina/efectos adversosRESUMEN
BACKGROUND: Safe, effective, and easily implementable treatments that reduce the progression of respiratory failure in COVID-19 are urgently needed. Despite the increased adoption of prone positioning during the pandemic, the effectiveness of this technique on progression of respiratory failure among nonintubated patients is unclear. RESEARCH QUESTION: What is the effectiveness of smartphone-guided self-prone positioning recommendations and instructions compared with usual care in reducing progression of respiratory failure among nonintubated patients with COVID-19? STUDY DESIGN AND METHODS: Awake Prone Position for Early Hypoxemia in COVID-19 (APPEX-19) is a multicenter randomized clinical trial that randomized nonintubated adults with COVID-19 on < 6 L/min of supplemental oxygen to receive a smartphone-guided self-prone positioning intervention or usual care. The primary outcome was the composite of respiratory deterioration (an increase in supplemental oxygen requirement) or ICU transfer. Using a Bayesian statistical approach, the posterior probability of superiority within each treatment arm (superiority threshold 95%) was calculated. RESULTS: The trial was stopped early for slow enrollment. A total of 293 participants were included in the modified intention-to-treat analysis (159 self-prone positioning intervention and 134 usual care). Among participants who self-reported body positioning (n = 139 [70 intervention, 69 usual care]), 71.4% in the intervention arm and 59.4% in the usual care arm attempted prone positioning. Thirty-one participants (posterior mean, 24.7%; 95% credible interval, 18.6-31.4) receiving usual care and 32 participants (posterior mean, 22.1%; 95% credible interval, 16.6-28.1) receiving the self-prone positioning intervention experienced the primary outcome; the posterior probability of superiority for the self-prone positioning intervention was 72.1%, less than the 95% threshold for superiority. Adverse events occurred in 26.9% of participants in the usual care arm and in 11.9% of participants in the intervention arm. INTERPRETATION: Among nonintubated patients with COVID-19, smartphone-guided self-prone positioning recommendations and instructions did not promote strong adherence to prone positioning. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04344587; URL: www. CLINICALTRIALS: gov.
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COVID-19 , Insuficiencia Respiratoria , Adulto , Teorema de Bayes , Hospitales , Humanos , Oxígeno , Posición Prona , Insuficiencia Respiratoria/terapia , SARS-CoV-2 , Teléfono InteligenteRESUMEN
BACKGROUND: Several chronic conditions have been associated with a higher risk of severe coronavirus disease 2019 (COVID-19), including asthma. However, there are conflicting conclusions regarding risk of severe disease in this population. OBJECTIVE: To understand the impact of asthma on COVID-19 outcomes in a cohort of hospitalized patients and whether there is any association between asthma severity and worse outcomes. METHODS: We identified hospitalized patients with COVID-19 with confirmatory polymerase chain reaction testing with (n = 183) and without asthma (n = 1319) using International Classification of Diseases, Tenth Revision, codes between March 1 and December 30, 2020. We determined asthma maintenance medications, pulmonary function tests, highest historical absolute eosinophil count, and immunoglobulin E. Primary outcomes included death, mechanical ventilation, intensive care unit (ICU) admission, and ICU and hospital length of stay. Analysis was adjusted for demographics, comorbidities, smoking status, and timing of illness in the pandemic. RESULTS: In unadjusted analyses, we found no difference in our primary outcomes between patients with asthma and patients without asthma. However, in adjusted analyses, patients with asthma were more likely to have mechanical ventilation (odds ratio, 1.58; 95% confidence interval [CI], 1.02-2.44; P = .04), ICU admission (odds ratio, 1.58; 95% CI, 1.09-2.29; P = .02), longer hospital length of stay (risk ratio, 1.30; 95% CI, 1.09-1.55; P < .003), and higher mortality (hazard ratio, 1.53; 95% CI, 1.01-2.33; P = .04) compared with the non-asthma cohort. Inhaled corticosteroid use and eosinophilic phenotype were not associated with considerabledifferences. Interestingly, patients with moderate asthma had worse outcomes whereas patients with severe asthma did not. CONCLUSION: Asthma was associated with severe COVID-19 after controlling for other factors.
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Asma , COVID-19 , Asma/complicaciones , Asma/epidemiología , COVID-19/epidemiología , Hospitalización , Humanos , Unidades de Cuidados Intensivos , Pandemias , Estudios Retrospectivos , SARS-CoV-2RESUMEN
The optimal polymyxin B dosage needed to achieve an efficacy target of 50 to 100 mg · h/liter when treating multidrug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50 to 100 mg every 12 h. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents B1 and B2 were quantified using liquid chromatography mass spectrometry (LC-MS). Population PK (NONMEM software) analysis was performed using pooled polymyxin B1+B2 concentrations. Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21 to 57 years) and 58.0 kg (range 38.3 to 70.4 kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution being 2.09 liters/h and 12.7 liters, respectively, corresponding to a 4.1 h mean half-life (t1/2). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 h was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients, with acute kidney injury events in two patients. These events resolved within 2 to 4 days after discontinuing polymyxin B. Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.
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Antibacterianos , Fibrosis Quística , Polimixina B , Adulto , Antibacterianos/farmacocinética , Fibrosis Quística/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimixina B/farmacocinética , Estudios Prospectivos , Adulto JovenRESUMEN
The unprecedented public health burdens of coronavirus disease (COVID-19) have intensified the urgency of identifying effective, low-cost treatments that limit the need for advanced life support measures and improve clinical outcomes. However, personal protective equipment and staffing shortages, disease virulence, and infectivity have created significant barriers to traditional clinical trial practices. We present the novel design of a pragmatic, adaptive, multicenter, international, prospective randomized controlled clinical trial evaluating the safety and effectiveness of awake prone positioning in spontaneously breathing patients with COVID-19 (APPEX-19 [Awake Prone Position for Early Hypoxemia in COVID-19]). Key innovations of this trial include 1) a novel smartphone-based communication process that facilitates rapid enrollment and intervention delivery while allowing social distancing and conservation of personal protective equipment, 2) Bayesian response-adaptive randomization to allow preferential assignment to the most effective intervention and expedite trial completion compared with frequentist designs, 3) remote electronic collection of patient-reported outcomes and electronic medical record data, and 4) pragmatic prospective use of patient-reported data and data collected as part of routine clinical care. Clinical trial registered with www.clinicaltrials.gov (NCT04344587).
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COVID-19 , Vigilia , Teorema de Bayes , Humanos , Hipoxia , Estudios Multicéntricos como Asunto , Posición Prona , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Fibrosis is characterized by fibroblast activation, leading to matrix remodeling culminating in a stiff, type I collagen-rich fibrotic matrix. Alveolar epithelial cell (AEC) apoptosis is also a major feature of fibrogenesis, and AEC apoptosis is sufficient to initiate a robust lung fibrotic response. TGF-ß (transforming growth factor-ß) is a major driver of fibrosis and can induce both AEC apoptosis and fibroblast activation. We and others have previously shown that changes in extracellular matrix stiffness and composition can regulate the cellular response to TGF-ß. In the present study, we find that type I collagen signaling promotes TGF-ß-mediated fibroblast activation and inhibits TGF-ß-induced AEC death. Fibroblasts cultured on type I collagen or fibrotic decellularized lung matrix had augmented activation in response to TGF-ß, whereas AECs on cultured on type I collagen or fibrotic lung matrix were more resistant to TGF-ß-induced apoptosis. Both of these responses were mediated by integrin α2ß1, a major collagen receptor. AECs treated with an α2 integrin inhibitor or with deletion of α2 integrin had loss of collagen-mediated protection from apoptosis. We found that mice with fibroblast-specific deletion of α2 integrin were protected from fibrosis whereas mice with AEC-specific deletion of α2 integrin had more lung injury and a greater fibrotic response to bleomycin. Intrapulmonary delivery of an α2 integrin-activating collagen peptide inhibited AEC apoptosis in vitro and in vivo and attenuated the fibrotic response. These studies underscore the need for a thorough understanding of the divergent response to matrix signaling.
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Colágeno Tipo I/metabolismo , Integrina alfa2beta1/metabolismo , Fibrosis Pulmonar/metabolismo , Transducción de Señal , Células Epiteliales Alveolares/metabolismo , Animales , Apoptosis , Matriz Extracelular/metabolismo , Integrina alfa2beta1/agonistas , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Impaired plasminogen activation (PA) is causally related to the development of lung fibrosis. Prior studies demonstrate that enhanced PA in the lung limits the severity of scarring following injury and in vitro studies indicate that PA promotes matrix degradation and fibroblast apoptosis. These findings led us to hypothesize that increased PA in an in vivo model would enhance the resolution of established lung fibrosis in conjunction with increased myofibroblast apoptosis. METHODS: Transgenic C57BL/6 mice with doxycycline inducible lung-specific urokinase plasminogen activator (uPA) expression or littermate controls were treated (day 0) with bleomycin or saline. Doxycycline was initiated on days 1, 9, 14, or 21. Lung fibrosis, stiffness, apoptosis, epithelial barrier integrity, and inflammation were assessed. RESULTS: Protection from fibrosis with uPA upregulation from day 1 through day 28 was associated with reduced parenchymal stiffness as determined by atomic force microscopy. Initiation of uPA expression beginning in the late inflammatory or the early fibrotic phase reduced stiffness and fibrosis at day 28. Induction of uPA activity in mice with established fibrosis decreased lung collagen and lung stiffness while increasing myofibroblast apoptosis. Upregulation of uPA did not alter lung inflammation but was associated with improved epithelial cell homeostasis. CONCLUSION: Restoring intrapulmonary PA activity diminishes lung fibrogenesis and enhances the resolution of established lung fibrosis. This PA-mediated resolution is associated with increased myofibroblast apoptosis and improved epithelial cell homeostasis. These studies support the potential capacity of the lung to resolve existing scar in murine models.
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Regulación de la Expresión Génica , Pulmón/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Apoptosis , Bleomicina/farmacología , Colágeno/metabolismo , Doxiciclina/farmacología , Fibroblastos/metabolismo , Genotipo , Homeostasis , Hidroxiprolina/farmacología , Inflamación , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Progressive fibrosis is a complication of many chronic diseases, and collectively, organ fibrosis is the leading cause of death in the United States. Fibrosis is characterized by accumulation of activated fibroblasts and excessive deposition of extracellular matrix proteins, especially type I collagen. Extensive research has supported a role for matrix signaling in propagating fibrosis, but type I collagen itself is often considered an end product of fibrosis rather than an important regulator of continued collagen deposition. Type I collagen can activate several cell surface receptors, including α2ß1 integrin and discoidin domain receptor 2 (DDR2). We have previously shown that mice deficient in type I collagen have reduced activation of DDR2 and reduced accumulation of activated myofibroblasts. In the present study, we found that DDR2-null mice are protected from fibrosis. Surprisingly, DDR2-null fibroblasts have a normal and possibly exaggerated activation response to transforming growth factor-ß and do not have diminished proliferation compared with wild-type fibroblasts. DDR2-null fibroblasts are significantly more prone to apoptosis, in vitro and in vivo, than wild-type fibroblasts, supporting a paradigm in which fibroblast resistance to apoptosis is critical for progression of fibrosis. We have identified a novel molecular mechanism by which DDR2 can promote the activation of a PDK1 (3-phosphoinositide dependent protein kinase-1)/Akt survival pathway, and we have found that inhibition of PDK1 can augment fibroblast apoptosis. Furthermore, our studies demonstrate that DDR2 expression is heavily skewed to mesenchymal cells compared with epithelial cells and that idiopathic pulmonary fibrosis cells and tissue demonstrate increased activation of DDR2 and PDK1. Collectively, these findings identify a promising target for fibrosis therapy.
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Colágeno Tipo II/metabolismo , Receptor con Dominio Discoidina 2/metabolismo , Fibroblastos/metabolismo , Integrinas/metabolismo , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Animales , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen/métodos , Humanos , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Progressive pulmonary fibrosis is a devastating consequence of many acute and chronic insults to the lung. Lung injury leads to alveolar epithelial cell (AEC) death, destruction of the basement membrane, and activation of transforming growth factor-ß (TGF-ß). There is subsequent resolution of the injury and a coordinated and concurrent initiation of fibrosis. Both of these processes may involve activation of similar intracellular signaling pathways regulated in part by dynamic changes to the extracellular matrix. Matrix signaling can augment the profibrotic fibroblast response to TGF-ß. However, similar matrix/integrin signaling pathways may also be involved in the inhibition of ongoing TGF-ß-induced AEC apoptosis. Focal adhesion kinase (FAK) is an integrin-associated signaling molecule expressed by many cell types. We used mice with AEC-specific FAK deletion to isolate the epithelial aspect of integrin signaling in the bleomycin model of lung injury and fibrosis. Mice with AEC-specific deletion of FAK did not exhibit spontaneous lung injury but did have significantly greater terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling-positive cells (18.6 vs. 7.1) per ×200 field, greater bronchoalveolar lavage protein (3.2 vs. 1.8 mg/ml), and significantly greater death (77 vs. 19%) after bleomycin injury compared with littermate control mice. Within primary AECs, activated FAK directly associates with caspase-8 and inhibits activation of the caspase cascade resulting in less apoptosis in response to TGF-ß. Our studies support a model in which dynamic changes to the extracellular matrix after injury promote fibroblast activation and inhibition of epithelial cell apoptosis in response to TGF-ß through FAK activation potentially complicating attempts to nonspecifically target this pathway for antifibrotic therapy.