RESUMEN
Recent data from human studies and animal models have established roles for type II alveolar epithelial cell (AEC2) injury/apoptosis and monocyte/macrophage accumulation and activation in progressive lung fibrosis. Although the link between these processes is not well defined, we have previously shown that CD36-mediated uptake of apoptotic AEC2s by lung macrophages is sufficient to drive fibrosis. Importantly, apoptotic AEC2s are rich in oxidized phospholipids (oxPL), and amongst its multiple functions, CD36 serves as a scavenger receptor for oxPL. Recent studies have established a role for oxPLs in alveolar scarring, and we hypothesized that uptake and accrual of oxPL by CD36 would cause a macrophage phenotypic change that promotes fibrosis. To test this hypothesis, we treated wild-type and CD36-null mice with the oxPL derivative oxidized phosphocholine (POVPC) and found that CD36-null mice were protected from oxPL-induced scarring. Compared to WT mice, fewer macrophages accumulated in the lungs of CD36-null animals, and the macrophages exhibited a decreased accumulation of intracellular oxidized lipid. Importantly, the attenuated accrual of oxPL in CD36-null macrophages was associated with diminished expression of the profibrotic mediator, TGFß. Finally, the pathway linking oxPL uptake and TGFß expression was found to require CD36-mediated activation of Lyn kinase. Together, these observations elucidate a causal pathway that connects AEC2 injury with lung macrophage activation via CD36-mediated uptake of oxPL and suggest several potential therapeutic targets.
Asunto(s)
Fibrosis Pulmonar , Ratones , Humanos , Animales , Fibrosis Pulmonar/metabolismo , Fosfolípidos/metabolismo , Cicatriz/metabolismo , Macrófagos/metabolismo , Ratones Noqueados , Fibrosis , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Idiopathic hyperammonemia is a serious condition that can arise after induction of chemotherapy and is characterized by plasma ammonia levels greater than two times the normal upper limit but within the context of normal liver function. While this dangerous complication usually appears several weeks after the start of chemotherapy, we report a fatal case of idiopathic hyperammonemia that was detected only nine days after induction chemotherapy in a 22-year-old man with no liver pathology or other risks for hyperammonemia. The patient's initial emergent presentation was altered mental status. Laboratory workup showed acute monoblastic leukemia and radiological investigation showed cerebral hemorrhagic foci secondary to leukostasis. He received leukoreduction apheresis and he was started on induction chemotherapy with daunorubicin and cytarabine. On the ninth day of induction chemotherapy, it was noted that he developed worsening neurological findings. Investigations showed significant elevation in ammonia level and associated cerebral edema. Although hyperammonemia was mitigated, the patient's cerebral status worsened and he died 15 days after initial presentation. This case shows that critical hyperammonemia can occur quickly after chemotherapy induction and that strategies for preventing a rise in plasma ammonia are necessary.
RESUMEN
BACKGROUND: COVID-19 caused by severe acute respiratory syndrome coronavirus 2 most commonly manifests with fever and respiratory illness. The cardiovascular manifestations have become more prevalent but can potentially go unrecognized. We look to describe cardiac manifestations in three patients with COVID-19 using cardiac enzymes, electrocardiograms, and echocardiography. CASE SUMMARIES: The first patient, a 67-year-old Caucasian female with non-ischaemic dilated cardiomyopathy, presented with dyspnoea on exertion and orthopnoea 1 week after testing positive for COVID-19. Echocardiogram revealed large pericardial effusion with findings consistent with tamponade. A pericardial drain was placed, and fluid studies were consistent with viral pericarditis, treated with colchicine, hydroxychloroquine, and methylprednisolone. Follow-up echocardiograms showed apical hypokinesis, that later resolved, consistent with Takotsubo syndrome. The second patient, a 46-year-old African American male with obesity and type 2 diabetes mellitus presented with fevers, cough, and dyspnoea due to COVID-19. Clinical course was complicated with pulseless electrical activity arrest; he was found to have D-dimer and troponin elevation, and inferior wall ST elevation on ECG concerning for STEMI due to microemboli. The patient succumbed to the illness. The third patient, a 76-year-old African American female with hypertension, presented with diarrhoea, fever, and myalgia, and was found to be COVID-19 positive. Clinical course was complicated, with acute troponin elevation, decreased cardiac index, and severe hypokinesis of the basilar wall suggestive of reverse Takotsubo syndrome. The cardiac index improved after pronation and non-STEMI therapy; however, the patient expired due to worsening respiratory status. DISCUSSION: These case reports demonstrate cardiovascular manifestations of COVID-19 that required monitoring and urgent intervention.
RESUMEN
Type II alveolar epithelial cell (AEC) apoptosis is a prominent feature of fibrotic lung diseases and animal models of pulmonary fibrosis. While there is growing recognition of the importance of AEC injury and apoptosis as a causal factor in fibrosis, the underlying mechanisms that link these processes remain unknown. We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop lung fibrosis, confirming that AEC injury is sufficient to cause fibrosis. In the present study, we find that SPC-DTR mice develop increased activation of caspase 3/7 after initiation of diphtheria toxin treatment consistent with apoptosis within AECs. We also find evidence of efferocytosis, the uptake of apoptotic cells, by alveolar macrophages in this model. To determine the importance of efferocytosis in lung fibrosis, we treated cultured alveolar macrophages with apoptotic type II AECs and found that the uptake induced pro-fibrotic gene expression. We also found that the repetitive intrapulmonary administration of apoptotic type II AEC or MLE-12 cells induces lung fibrosis. Finally, mice lacking a key efferocytosis receptor, CD36, developed attenuated fibrosis in response to apoptotic MLE-12 cells. Collectively, these studies support a novel mechanism linking AEC apoptosis with macrophage pro-fibrotic activation via efferocytosis and reveal previously unrecognized therapeutic targets.
Asunto(s)
Células Epiteliales Alveolares/patología , Apoptosis/genética , Macrófagos Alveolares/patología , Fagocitosis , Alveolos Pulmonares/patología , Fibrosis Pulmonar/patología , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/trasplante , Animales , Líquido del Lavado Bronquioalveolar/química , Antígenos CD36/deficiencia , Antígenos CD36/genética , Antígenos CD36/inmunología , Caspasa 3/genética , Caspasa 3/inmunología , Caspasa 7/genética , Caspasa 7/inmunología , Línea Celular , Toxina Diftérica/administración & dosificación , Regulación de la Expresión Génica , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina/inmunología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Activación de Macrófagos , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Cultivo Primario de Células , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/inmunología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/inmunología , Proteína C Asociada a Surfactante Pulmonar , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Transducción de SeñalRESUMEN
The coordinated iron structure and ferrochelatase binding surface of human frataxin have been characterized to provide insight into the protein's ability to serve as the iron chaperone during heme biosynthesis.
Asunto(s)
Ferroquelatasa/metabolismo , Proteínas de Unión a Hierro/metabolismo , Hierro/metabolismo , Cristalografía por Rayos X , Hemo/biosíntesis , Humanos , Espectroscopía de Resonancia Magnética , Chaperonas Moleculares/metabolismo , Propiedades de Superficie , FrataxinaRESUMEN
Friedreich's ataxia, an autosomal cardio- and neurodegenerative disorder that affects 1 in 50,000 humans, is caused by decreased levels of the protein frataxin. Although frataxin is nuclear-encoded, it is targeted to the mitochondrial matrix and necessary for proper regulation of cellular iron homeostasis. Frataxin is required for the cellular production of both heme and iron-sulfur (Fe-S) clusters. Monomeric frataxin binds with high affinity to ferrochelatase, the enzyme involved in iron insertion into porphyrin during heme production. Monomeric frataxin also binds to Isu, the scaffold protein required for assembly of Fe-S cluster intermediates. These processes (heme and Fe-S cluster assembly) share requirements for iron, suggesting that monomeric frataxin might function as the common iron donor. To provide a molecular basis to better understand frataxin's function, we have characterized the binding properties and metal-site structure of ferrous iron bound to monomeric yeast frataxin. Yeast frataxin is stable as an iron-loaded monomer, and the protein can bind two ferrous iron atoms with micromolar binding affinity. Frataxin amino acids affected by the presence of iron are localized within conserved acidic patches located on the surfaces of both helix-1 and strand-1. Under anaerobic conditions, bound metal is stable in the high-spin ferrous state. The metal-ligand coordination geometry of both metal-binding sites is consistent with a six-coordinate iron-(oxygen/nitrogen) based ligand geometry, surely constructed in part from carboxylate and possibly imidazole side chains coming from residues within these conserved acidic patches on the protein. On the basis of our results, we have developed a model for how we believe yeast frataxin interacts with iron.