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1.
Eur Respir J ; 63(1)2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37973175

RESUMO

RATIONALE: Whole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP. METHODS: 18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline WLL. Outcome measures included additional unscheduled "rescue" WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group. RESULTS: The primary end-point of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar-arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported. CONCLUSIONS: This long-term, prospective, randomised trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP.


Assuntos
Doenças Autoimunes , Proteinose Alveolar Pulmonar , Surfactantes Pulmonares , Humanos , Proteinose Alveolar Pulmonar/tratamento farmacológico , Proteinose Alveolar Pulmonar/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Estudos Prospectivos , Administração por Inalação , Resultado do Tratamento , Doenças Autoimunes/tratamento farmacológico , Surfactantes Pulmonares/uso terapêutico , Lavagem Broncoalveolar , Oxigênio/uso terapêutico , Tensoativos/uso terapêutico , Biomarcadores
2.
N Engl J Med ; 383(17): 1635-1644, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32897035

RESUMO

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. METHODS: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 µg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. RESULTS: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. CONCLUSIONS: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Proteinose Alveolar Pulmonar/tratamento farmacológico , Administração por Inalação , Adulto , Doenças Autoimunes/fisiopatologia , Doenças Autoimunes/terapia , Lavagem Broncoalveolar , Método Duplo-Cego , Esquema de Medicação , Tolerância ao Exercício , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteinose Alveolar Pulmonar/fisiopatologia , Proteinose Alveolar Pulmonar/terapia , Troca Gasosa Pulmonar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Teste de Caminhada
3.
Am J Respir Crit Care Med ; 205(9): 1016-1035, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35227171

RESUMO

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency. It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome. The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years. Digital clubbing, fever, and hemoptysis are not typical, and the latter two indicate that intercurrent infection may be present. Low prevalence and nonspecific clinical, radiological, and laboratory findings commonly lead to misdiagnosis as pneumonia and substantially delay an accurate diagnosis. The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death. Two decades of research have raised autoimmune PAP from obscurity to a paradigm of molecular pathogenesis-based diagnostic and therapeutic development. Pathogenesis is driven by GM-CSF (granulocyte/macrophage colony-stimulating factor) autoantibodies, which are present at high concentrations in blood and tissues and form the basis of an accurate, commercially available diagnostic blood test with sensitivity and specificity of 100%. Although whole-lung lavage remains the first-line therapy, inhaled GM-CSF is a promising pharmacotherapeutic approach demonstrated in well-controlled trials to be safe, well tolerated, and efficacious. Research has established GM-CSF as a pulmonary regulatory molecule critical to surfactant homeostasis, alveolar stability, lung function, and host defense.


Assuntos
Doenças Autoimunes , Proteinose Alveolar Pulmonar , Adulto , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Lavagem Broncoalveolar , Criança , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/patologia , Proteinose Alveolar Pulmonar/terapia
4.
Am J Physiol Lung Cell Mol Physiol ; 322(3): L438-L448, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35043685

RESUMO

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder caused by recessive mutations in GM-CSF receptor subunit α/ß genes (CSF2RA/CSF2RB, respectively) characterized by impaired GM-CSF-dependent surfactant clearance by alveolar macrophages (AMs) resulting in alveolar surfactant accumulation and hypoxemic respiratory failure. Because hPAP is caused by CSF2RA mutations in most patients, we created an animal model of hPAP caused by Csf2ra gene disruption (Csf2ra-/- mice) and evaluated the effects on AMs and lungs. Macrophages from Csf2ra-/- mice were unable to bind and clear GM-CSF, did not exhibit GM-CSF signaling, and had functional defects in phagocytosis, cholesterol clearance, and surfactant clearance. Csf2ra-/- mice developed a time-dependent, progressive lung disease similar to hPAP in children caused by CSF2RA mutations with respect to the clinical, physiological, histopathological, biochemical abnormalities, biomarkers of PAP lung disease, and clinical course. In contrast, Csf2ra+/- mice had functionally normal AMs and no lung disease. Pulmonary macrophage transplantation (PMT) without myeloablation resulted in long-term engraftment, restoration of GM-CSF responsiveness to AMs, and a safe and durable treatment effect that lasted for the duration of the experiment (6 mo). Results demonstrate that homozygous (but not heterozygous) Csf2ra gene ablation caused hPAP identical to hPAP in children with CSF2RA mutations, identified AMs as the cellular site of hPAP pathogenesis in Csf2ra-/- mice, and have implications for preclinical studies supporting the translation of PMT as therapy of hPAP in humans.


Assuntos
Proteinose Alveolar Pulmonar , Surfactantes Pulmonares , Animais , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Macrófagos Alveolares/metabolismo , Camundongos , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/metabolismo , Surfactantes Pulmonares/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Tensoativos/metabolismo
5.
Ann Rheum Dis ; 81(5): 653-661, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35264321

RESUMO

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1).


Assuntos
Arterite de Células Gigantes , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Arterite de Células Gigantes/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Prednisona/efeitos adversos , Resultado do Tratamento
6.
Occup Environ Med ; 79(8): 550-556, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35414568

RESUMO

OBJECTIVES: To determine whether engineering controls and respiratory protection had measurable short-term impact on indium exposure and respiratory health among current indium-tin oxide production and reclamation facility workers. METHODS: We documented engineering controls implemented following our 2012 evaluation and recorded respirator use in 2012 and 2014. We measured respirable indium (Inresp) and plasma indium (InP) in 2012 and 2014, and calculated change in Inresp (∆Inresp) and InP (∆InP) by the 13 departments. We assessed symptoms, lung function, serum biomarkers of interstitial lung disease (Krebs von den Lungen (KL)-6 and surfactant protein (SP)-D) and chest high-resolution CT at both time points and evaluated workers who participated in both 2012 and 2014 for changes in health outcomes (new, worsened or improved). RESULTS: Engineering controls included installation of local exhaust ventilation in both grinding departments (Rotary and Planar) and isolation of the Reclaim department. Respiratory protection increased in most (77%) departments. ∆InP and ∆Inresp often changed in parallel by department. Among 62 workers participating in both 2012 and 2014, 18 (29%) had new or worsening chest symptoms and 2 (3%) had functional decline in lung function or radiographic progression, but average KL-6 and SP-D concentrations decreased, and no cases of clinical indium lung disease were recognised. CONCLUSIONS: Increased engineering controls and respiratory protection can lead to decreased Inresp, InP and biomarkers of interstitial lung disease among workers in 2 years. Ongoing medical monitoring of indium-exposed workers to confirm the longer-term effectiveness of preventive measures is warranted.


Assuntos
Doenças Pulmonares Intersticiais , Exposição Ocupacional , Biomarcadores , Seguimentos , Humanos , Índio/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Proteína D Associada a Surfactante Pulmonar , Compostos de Estanho
7.
Am J Respir Cell Mol Biol ; 62(1): 87-94, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310562

RESUMO

Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage-colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+ mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55-90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+ mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.


Assuntos
Doenças Genéticas Inatas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Alvéolos Pulmonares/metabolismo , Animais , Enfisema/metabolismo , Células Epiteliais/metabolismo , Hiperplasia/metabolismo , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Policitemia/metabolismo , Fator de Transcrição STAT5/metabolismo , Fumar/metabolismo
8.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L137-L147, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159969

RESUMO

Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro. Cytokines were measured in the apical supernatant by Luminex, and the effect on the HBE transcriptome was assessed by RNA sequencing. NETs consistently stimulated IL-8, TNF-α, and IL-1α secretion by HBEs from multiple donors, with variable effects on other cytokines (IL-6, G-CSF, and GM-CSF). Expression of HBE RNAs encoding IL-1 family cytokines, particularly IL-36 subfamily members, was increased in response to NETs. NET exposure in the presence of anakinra [recombinant human IL-1 receptor antagonist (rhIL-1RA)] dampened NET-induced changes in IL-8 and TNF-α proteins as well as IL-36α RNA. rhIL-36RA limited the increase in expression of proinflammatory cytokine RNAs in HBEs exposed to NETs. NETs selectively upregulate an IL-1 family cytokine response in HBEs, which enhances IL-8 production and is limited by rhIL-1RA. The present findings describe a unique mechanism by which NETs may contribute to inflammation in human lung disease in vivo. NET-driven IL-1 signaling may represent a novel target for modulating inflammation in diseases characterized by a substantial NET burden.


Assuntos
Brônquios/citologia , Células Epiteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-1/metabolismo , Interleucina-8/metabolismo , Adulto , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Elastase de Leucócito/metabolismo , Peroxidase/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos
9.
Haematologica ; 105(4): 1147-1157, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31289207

RESUMO

Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using Csf2rb-/- mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff+ material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c+/SiglecF+ cells in the lungs from a CD11c-/SiglecF+ progenitor population within four weeks after transplantation. Based on these data, we suggest hematopoietic stem cell-based gene therapy as an effective and cause-directed treatment approach for herPAP.


Assuntos
Proteinose Alveolar Pulmonar , Animais , Modelos Animais de Doenças , Terapia Genética , Células-Tronco Hematopoéticas , Macrófagos Alveolares , Camundongos , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/terapia
10.
Nature ; 514(7523): 450-4, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25274301

RESUMO

Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor-ß-deficient (Csf2rb(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.


Assuntos
Transplante de Células , Subunidade beta Comum dos Receptores de Citocinas/genética , Terapia Genética , Pulmão/citologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/transplante , Proteinose Alveolar Pulmonar/terapia , Animais , Separação Celular , Subunidade beta Comum dos Receptores de Citocinas/deficiência , Feminino , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/patologia , Fatores de Tempo
11.
Mol Ther ; 27(9): 1597-1611, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31326401

RESUMO

Hereditary pulmonary alveolar proteinosis (PAP) is a genetic lung disease characterized by surfactant accumulation and respiratory failure arising from disruption of GM-CSF signaling. While mutations in either CSF2RA or CSF2RB (encoding GM-CSF receptor α or ß chains, respectively) can cause PAP, α chain mutations are responsible in most patients. Pulmonary macrophage transplantation (PMT) is a promising new cell therapy in development; however, no studies have evaluated this approach for hereditary PAP (hPAP) caused by Csf2ra mutations. Here, we report on the preclinical safety, tolerability, and efficacy of lentiviral-vector (LV)-mediated Csf2ra expression in macrophages and PMT of gene-corrected macrophages (gene-PMT therapy) in Csf2ra gene-ablated (Csf2ra-/-) mice. Gene-PMT therapy resulted in a stable transgene integration and correction of GM-CSF signaling and functions in Csf2ra-/- macrophages in vitro and in vivo and resulted in engraftment and long-term persistence of gene-corrected macrophages in alveoli; restoration of pulmonary surfactant homeostasis; correction of PAP-specific cytologic, histologic, and biomarker abnormalities; and reduced inflammation associated with disease progression in untreated mice. No adverse consequences of gene-PMT therapy in Csf2ra-/- mice were observed. Results demonstrate that gene-PMT therapy of hPAP in Csf2ra-/- mice was highly efficacious, durable, safe, and well tolerated.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Terapia Genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/transplante , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/terapia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Animais , Proliferação de Células , Terapia Baseada em Transplante de Células e Tecidos/métodos , Modelos Animais de Doenças , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/genética , Imunofenotipagem , Lentivirus/genética , Camundongos , Camundongos Knockout , Proteinose Alveolar Pulmonar/diagnóstico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais , Transdução Genética
12.
Am J Respir Crit Care Med ; 200(10): 1267-1281, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31215789

RESUMO

Rationale: Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly.Objectives: To test the hypothesis that CTRD is caused by inherited or de novo mutations in genes required for normal tracheal development.Methods: CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed in children with CTRD and their biological parents ("trio analysis") to identify gene variants in patients with CTRD. Mutations were confirmed by Sanger sequencing, and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison with the effects of targeted deletion of murine homologs important to tracheal development in mice.Measurements and Main Results: The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six de novo, three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD. De novo variants were identified in SHH (Sonic Hedgehog), and inherited variants were identified in HSPG2 (perlecan), ROR2 (receptor tyrosine kinase-like orphan receptor 2), and WLS (Wntless), genes involved in morphogenetic pathways known to mediate tracheoesophageal development in mice.Conclusions: The results of the present study demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and Wnt signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.


Assuntos
Mutação/genética , Anormalidades do Sistema Respiratório/genética , Traqueia/anormalidades , Animais , Estudos de Coortes , Modelos Animais de Doenças , Humanos , Camundongos , Anormalidades do Sistema Respiratório/diagnóstico , Anormalidades do Sistema Respiratório/cirurgia
13.
Chron Respir Dis ; 17: 1479973119900612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31984768

RESUMO

We investigated the relationship between self-reported adherence to pancreatic enzyme replacement therapy (PERT), nutritional status, and all-cause hospitalization in cystic fibrosis (CF) patients with a record of PERT use. Association of self-reported annual PERT use rate (adherence) with annual hospital admission rate (HAR) and annual total hospital nights (THNs) were analyzed for 5301 children (2000-2012) and 13,989 adults (2000-2013) from the CF Foundation Patient Registry. Multivariate linear regression was used to determine the association of HAR and THN with mean annual PERT use rate, cumulative PERT use rate, mean body mass index (BMI) (adult) or BMI percentile (pediatric), age, and sex. The median annual PERT use rate was 87% in children and 80% in adults. Statistically, higher annual PERT use, longer cumulative PERT, and higher BMI percentile (children) or BMI (adults) were significantly (p < 0.0001) associated with lower annual HAR and fewer annual THN in children and adults. Female sex was associated with higher annual HAR and more annual THN in children and adults (p < 0.05). Results indicate self-reported adherence to PERT, increased BMI, and male sex were associated with fewer hospital admissions and annual hospital nights in CF patients.


Assuntos
Índice de Massa Corporal , Fibrose Cística , Terapia de Reposição de Enzimas/métodos , Hospitalização/estatística & dados numéricos , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Adulto , Fatores Etários , Criança , Fibrose Cística/epidemiologia , Fibrose Cística/terapia , Feminino , Humanos , Masculino , Estado Nutricional , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Autorrelato , Fatores Sexuais , Estados Unidos/epidemiologia
14.
Eur Respir J ; 53(4)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30846465

RESUMO

INTRODUCTION: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. METHODS: MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV1; 51-70% versus ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. RESULTS: In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV1 slope -17±3 versus -3±3 mL·month-1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 versus -1±2 mL·month-1; p<0.0001) and post-menopausal patients (-3±3 versus 6±3 mL·month-1; p=0.04) exhibited a beneficial response in mean±se FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL-1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. CONCLUSIONS: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Sirolimo/uso terapêutico , Adulto , Povo Asiático , Broncodilatadores/uso terapêutico , Estudos de Coortes , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Neoplasias Pulmonares/fisiopatologia , Linfangioleiomiomatose/fisiopatologia , Pessoa de Meia-Idade , Pós-Menopausa , Pré-Menopausa , Resultado do Tratamento , População Branca
15.
Am J Respir Cell Mol Biol ; 59(1): 45-55, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29365277

RESUMO

IFN-ß is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-ß for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-ß 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-ß reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-ß improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.


Assuntos
Interferon beta/uso terapêutico , Macrófagos Alveolares/patologia , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/fisiopatologia , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon beta/farmacologia , Lesão Pulmonar/sangue , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/fisiopatologia , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Pneumonia/sangue , Pneumonia/complicações , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/tratamento farmacológico , Sepse/sangue , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento
16.
Clin Infect Dis ; 66(8): 1239-1245, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29126235

RESUMO

Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.


Assuntos
Anticorpos Neutralizantes/sangue , Autoanticorpos/sangue , Interferon gama/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Micobactérias não Tuberculosas/imunologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Síndromes de Imunodeficiência , Japão , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Estudos Retrospectivos
17.
Lancet ; 389(10080): 1710-1718, 2017 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-28259484

RESUMO

BACKGROUND: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS: We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS: Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. INTERPRETATION: Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. FUNDING: Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.


Assuntos
Doença de Crohn/complicações , Adalimumab/uso terapêutico , Adolescente , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Estudos de Coortes , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/microbiologia , Progressão da Doença , Feminino , Microbioma Gastrointestinal , Humanos , Infliximab/uso terapêutico , Obstrução Intestinal/etiologia , Masculino , Prognóstico , Pontuação de Propensão , Estudos Prospectivos , Medição de Risco/métodos , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidores
18.
J Pediatr Gastroenterol Nutr ; 66(5): 767-772, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29216019

RESUMO

OBJECTIVES: Elevated granulocyte-macrophage colony-stimulating factor auto-antibodies (GM-CSF Ab) are associated with increased intestinal permeability and stricturing behavior in Crohn disease (CD). We tested for familial association of serum GM-CSF Ab level in CD and ulcerative colitis (UC) families. METHODS: Serum GM-CSF Ab concentration was determined in 230 pediatric CD probands and 404 of their unaffected parents and siblings, and 45 UC probands and 71 of their unaffected parents and siblings. A linear mixed effects model was used to test for familial association. The intra-class correlation coefficient (ICC) was used to determine the degree of association of the serum GM-CSF Ab level within families in comparison with the degree of association among families. RESULTS: The median (IQR) serum GM-CSF Ab concentration was higher in CD probands than in UC probands (1.5 [0.5,5.4] µg/mL vs 0.7 [0.3, 1.6] µg/mL, P = 0.0002). The frequency of elevated serum GM-CSF Ab concentration ≥1.6 µg/mL was increased in unaffected siblings of CD probands with elevated GM-CSF Ab, compared with unaffected siblings of CD probands without elevated GM-CSF Ab (33% vs 13%, respectively, P = 0.04). A similar result was observed within UC families. In families of CD patients, the mean (95th CI) ICC was equal to 0.153 (0.036, 0.275), P = 0.001, whereas in families of UC patients, the mean (95th CI) ICC was equal to 0.27 (0.24, 0.31), P = 0.047. CONCLUSIONS: These data confirmed familial association of serum GM-CSF Ab levels. This could be accounted for by either genetic or environmental factors shared within the family.


Assuntos
Autoanticorpos/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Doenças Inflamatórias Intestinais/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Doenças Inflamatórias Intestinais/imunologia , Masculino , Fenótipo , Adulto Jovem
20.
Blood ; 125(2): 215-6, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25573969

RESUMO

In this issue of Blood, Iriguchi et al report that T-lymphocyte­restricted overexpression of T-bet causes a maturational arrest in mononuclear phagocyte lineage cells and severe secondary pulmonary alveolar proteinosis (PAP).


Assuntos
Hematopoese/imunologia , Macrófagos/imunologia , Células Mieloides/imunologia , Proteinose Alveolar Pulmonar/imunologia , Proteínas com Domínio T/biossíntese , Animais
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