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1.
Circulation ; 141(2): 132-146, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31928435

RESUMO

BACKGROUND: Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known. METHODS: We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (Fbn1C1039G/+), gene-edited MFS pigs (FBN1Glu433AsnfsX98/+), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages (Fbn1C1039G/+;Ccr2RFP/RFP) were generated to determine the requirements of recruited macrophages to MVD progression. RESULTS: MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity. CONCLUSIONS: All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.


Assuntos
Doenças das Valvas Cardíacas/patologia , Síndrome de Marfan/patologia , Monócitos/metabolismo , Animais , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Cães , Matriz Extracelular/metabolismo , Fibrilina-1/genética , Fibrilina-1/metabolismo , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Síndrome de Marfan/complicações , Síndrome de Marfan/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Valva Mitral/metabolismo , Valva Mitral/fisiopatologia , Monócitos/citologia , Suínos
2.
Shock ; 46(5): 541-548, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27172154

RESUMO

Currently, over 10% of the US population is taking antidepressants. Numerous antidepressants such as amitriptyline are known to inhibit acid sphingomyelinase (Asm), an enzyme that is known to mediate leukocyte function and homeostasis. Severe burn injury can lead to an immunosuppressive state that is characterized by decreased leukocyte function and numbers as well as increased susceptibility to infection. Based upon the intersection of these facts, we hypothesized that amitriptyline-treated, scald-injured mice would have an altered immune response to injury as compared with untreated scald mice. Prior to burn, mice were pretreated with amitriptyline. Drug- or saline-treated mice were subjected full thickness dorsal scald- or sham-injury. Immune cells from spleen, thymus, and bone marrow were subsequently harvested and characterized. We first observed that amitriptyline prior to burn injury increased body mass loss and spleen contraction. Both amitriptylinetreatment and burn injury resulted in a 40% decrease of leukocyte Asm activity. Following scald injury, we demonstrate increased reduction of lymphocyte precursors in the bone marrow and thymus, as well as mature leukocytes in the spleen in mice that were treated with amitriptyline. We also demonstrate that amitriptyline treatment prior to injury reduced neutrophil accumulation following peptidoglycan stimulus in scald-injured mice. These data show that Asm alterations can play a significant role in mediating alterations to the immune system after injury. The data further suggest that those taking antidepressants may be at a higher risk for complications following burn injury.


Assuntos
Amitriptilina/uso terapêutico , Queimaduras/tratamento farmacológico , Queimaduras/imunologia , Animais , Antidepressivos Tricíclicos/uso terapêutico , Western Blotting , Queimaduras/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Terapia de Imunossupressão , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo
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