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1.
Artigo em Inglês | MEDLINE | ID: mdl-37804247

RESUMO

The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in the lung-particularly timely given the Corona Virus Immune Disease-2019 pandemic-along with the role of metabolism and nutrient-regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest.


Assuntos
Envelhecimento , Múltiplas Afecções Crônicas , Humanos , Envelhecimento/fisiologia , Inflamação , Pulmão , Gerociência
2.
Ann Thorac Surg ; 102(4): e339-41, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27645977

RESUMO

A third of lung recipients have preexisting antibodies against nonhuman leukocyte self-antigens (nHAbs) present in the lung tissue. These nHAbs also form de novo in about 70% of patients within 3 years after transplantation. Both preexisting and de novo nHAbs can cause murine lung allograft dysfunction. However, their role in human transplantation remains unclear. We report hyperacute rejection after right lung transplant in a recipient with preexisting nHAbs. The recipient of the left lung from the same donor had an uneventful initial course, but de novo nHAbs developed at 3 weeks, leading to acute humoral rejection. Both patients were successfully treated with antibody-directed therapies.


Assuntos
Autoanticorpos/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Imunoterapia/métodos , Transplante de Pulmão/efeitos adversos , Idoso , Aloenxertos , Biópsia por Agulha , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Radiografia Torácica/métodos , Medição de Risco , Estudos de Amostragem , Resultado do Tratamento
3.
Am J Respir Crit Care Med ; 189(1): 96-103, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24033344

RESUMO

Recent discoveries indicate that disorders of protein folding and degradation play a particularly important role in the development of lung diseases and their associated complications. The overarching purpose of the National Heart, Lung, and Blood Institute workshop on "Malformed Protein Structure and Proteostasis in Lung Diseases" was to identify mechanistic and clinical research opportunities indicated by these recent discoveries in proteostasis science that will advance our molecular understanding of lung pathobiology and facilitate the development of new diagnostic and therapeutic strategies for the prevention and treatment of lung disease. The workshop's discussion focused on identifying gaps in scientific knowledge with respect to proteostasis and lung disease, discussing new research advances and opportunities in protein folding science, and highlighting novel technologies with potential therapeutic applications for diagnosis and treatment.


Assuntos
Pneumopatias/etiologia , Deficiências na Proteostase/etiologia , Envelhecimento , Pesquisa Biomédica , Descoberta de Drogas , Educação , Humanos , Pneumopatias/diagnóstico , Pneumopatias/terapia , National Heart, Lung, and Blood Institute (U.S.) , Dobramento de Proteína/efeitos dos fármacos , Deficiências na Proteostase/diagnóstico , Deficiências na Proteostase/tratamento farmacológico , Deficiências na Proteostase/terapia , Estados Unidos
4.
J Histochem Cytochem ; 54(6): 665-72, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16714422

RESUMO

Two epithelial cell types cover the alveolar surface of the lung. Type II alveolar epithelial cells produce surfactant and, during development or following wounding, give rise to type I cells that are involved in gas exchange and alveolar fluid homeostasis. In culture, freshly isolated alveolar type II cells assume a more squamous (type I-like) appearance within 4 days after plating. They assemble numerous focal adhesions that associate with the actin cytoskeleton at the cell margins. These alveolar epithelial cells lose expression of type II cell markers including SP-C and after 4 days in culture express the type I cell marker T1alpha. Those cells that express T1alpha also deposit fibers of laminin-311 in their matrix. The latter appears to be related to their development of a type I phenotype because freshly isolated, primary type I cells also assemble laminin-311-rich fibers in vitro. A beta1 integrin antibody antagonist inhibits the assembly of laminin-311 matrix fibers. Moreover, the formation of laminin fibers is dependent on the activity of the small GTPases and is perturbed by ML-7, a myosin light chain kinase inhibitor. In summary, our data indicate that assembly of laminin-311 fibers by lung epithelial cells is integrin and actin cytoskeleton dependent, and that these fibers are characteristic of type I alveolar cells.


Assuntos
Laminina/metabolismo , Alvéolos Pulmonares/metabolismo , Mucosa Respiratória/metabolismo , Citoesqueleto de Actina/ultraestrutura , Actinas/fisiologia , Animais , Azepinas/farmacologia , Células Cultivadas , Citoesqueleto/fisiologia , Eletroforese em Gel de Poliacrilamida , Matriz Extracelular/metabolismo , Matriz Extracelular/ultraestrutura , Immunoblotting , Integrina beta1/fisiologia , Laminina/ultraestrutura , Masculino , Glicoproteínas de Membrana/metabolismo , Microscopia de Fluorescência , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Miosinas/fisiologia , Naftalenos/farmacologia , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/ultraestrutura , Ratos , Ratos Sprague-Dawley , Mucosa Respiratória/citologia , Mucosa Respiratória/ultraestrutura
5.
J Cell Sci ; 118(Pt 12): 2557-66, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15928048

RESUMO

Mechanical ventilation is a valuable treatment regimen for respiratory failure. However, mechanical ventilation (especially with high tidal volumes) is implicated in the initiation and/or exacerbation of lung injury. Hence, it is important to understand how the cells that line the inner surface of the lung [alveolar epithelial cells (AECs)] sense cyclic stretching. Here, we tested the hypothesis that matrix molecules, via their interaction with surface receptors, transduce mechanical signals in AECs. We first determined that rat AECs secrete an extracellular matrix (ECM) rich in anastamosing fibers composed of the alpha3 laminin subunit, complexed with beta1 and gamma1 laminin subunits (i.e. laminin-6), and perlecan by a combination of immunofluorescence microscopy and immunoblotting analyses. The fibrous network exhibits isotropic expansion when exposed to cyclic stretching (30 cycles per minute, 10% strain). Moreover, this same stretching regimen activates mitogen-activated-protein kinase (MAPK) in AECs. Stretch-induced MAPK activation is not inhibited in AECs treated with antagonists to alpha3 or beta1 integrin. However, MAPK activation is significantly reduced in cells treated with function-inhibiting antibodies against the alpha3 laminin subunit and dystroglycan, and when dystroglycan is knocked down in AECs using short hairpin RNA. In summary, our results support a novel mechanism by which laminin-6, via interaction with dystroglycan, transduces a mechanical signal initiated by stretching that subsequently activates the MAPK pathway in rat AECs. These results are the first to indicate a function for laminin-6. They also provide novel insight into the role of the pericellular environment in dictating the response of epithelial cells to mechanical stimulation and have broad implications for the pathophysiology of lung injury.


Assuntos
Distroglicanas/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Integrinas/metabolismo , Laminina/química , Laminina/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Matriz Extracelular/metabolismo , Pulmão/citologia , Masculino , Glicoproteínas de Membrana/metabolismo , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Ligação Proteica , Estrutura Quaternária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Transporte Proteico , Ratos , Ratos Sprague-Dawley
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