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1.
Am J Respir Cell Mol Biol ; 59(5): 623-634, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29894205

RESUMO

Mechanical ventilation with O2-rich gas (MV-O2) inhibits alveologenesis and lung growth. We previously showed that MV-O2 increased elastase activity and apoptosis in lungs of newborn mice, whereas elastase inhibition by elafin suppressed apoptosis and enabled lung growth. Pilot studies suggested that MV-O2 reduces lung expression of prosurvival factors phosphorylated epidermal growth factor receptor (pEGFR) and Krüppel-like factor 4 (Klf4). Here, we sought to determine whether apoptosis and lung growth arrest evoked by MV-O2 reflect disrupted pEGFR-Klf4 signaling, which elafin treatment preserves, and to assess potential biomarkers of bronchopulmonary dysplasia (BPD). Five-day-old mice underwent MV with air or 40% O2 for 8-24 hours with or without elafin treatment. Unventilated pups served as controls. Immunoblots were used to assess lung pEGFR and Klf4 proteins. Cultured MLE-12 cells were exposed to AG1478 (EGFR inhibitor), Klf4 siRNA, or vehicle to assess effects on proliferation, apoptosis, and EGFR regulation of Klf4. Plasma elastase and elafin levels were measured in extremely premature infants. In newborn mice, MV with air or 40% O2 inhibited EGFR phosphorylation and suppressed Klf4 protein content in lungs (vs. unventilated controls), yielding increased apoptosis. Elafin treatment inhibited elastase, preserved lung pEGFR and Klf4, and attenuated the apoptosis observed in lungs of vehicle-treated mice. In MLE-12 studies, pharmacological inhibition of EGFR and siRNA suppression of Klf4 increased apoptosis and reduced proliferation, and EGFR inhibition decreased Klf4. Plasma elastase levels were more than twofold higher, without a compensating increase of plasma elafin, in infants with BPD, compared to infants without BPD. These findings indicate that pEGFR-Klf4 is a novel prosurvival signaling pathway in lung epithelium that MV disrupts. Elafin preserves pEGFR-Klf4 signaling and inhibits apoptosis, thereby enabling lung growth during MV. Together, our animal and human data raise the question: would elastase inhibition prevent BPD in high-risk infants exposed to MV-O2?


Assuntos
Apoptose/efeitos dos fármacos , Displasia Broncopulmonar/tratamento farmacológico , Elafina/farmacologia , Receptores ErbB/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Respiração Artificial/efeitos adversos , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Sobrevivência Celular , Células Cultivadas , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Fator 4 Semelhante a Kruppel , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos BALB C , Organogênese , Elastase Pancreática/metabolismo , Inibidores de Proteases/farmacologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Transdução de Sinais
2.
Strahlenther Onkol ; 193(9): 756-760, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28567504

RESUMO

INTRODUCTION: Considering that the number of malignant diseases in patients over 65 years of age is increasing, it often occurs that patients who carry a cardiac implanted electronic device must undergo radiotherapy. Ionizing radiation can disturb the function of the implantable cardioverter-defibrillator (ICD). As a result of this, an update of the DEGRO/DKG guidelines for radiotherapy of this patient group has been published. METHODS: We report the case of a patient with an ICD and T­lymphoblastic lymphoma with cardiac involvement, who received i.a. a total body irradiation with 8 Gy followed by a consolidating radiotherapy of the pericardium with 14 Gy as well as additional radiotherapy courses after consecutive recurrences. For the purposes of the treatment, the antitachyarrhythmia (ATA) therapy was deactivated and temporarily replaced through a life vest. RESULTS: According to the current DEGRO guidelines for irradiation of patients with cardiac implanted electronic devices, a categorization of the patient in the "high-risk" group was made. Furthermore, regular telemetric checks of the ICD device were performed before and after treatment. Despite unavailable declaration of the manufacturer regarding the cumulative tolerable dose and DEGRO recommendation for a cumulative dose <2 Gy, the aftercare was unproblematic and normal values were assessed for all relevant ICD parameters, despite a cumulative dose >10 Gy in the device. CONCLUSION: This case shows that if the cardiac implanted electronic devices are not directly irradiated und the energy used is reduced to 6 MV, irradiation-induced damage is less likely and can possibly be prevented.


Assuntos
Desfibriladores Implantáveis , Análise de Falha de Equipamento , Neoplasias Cardíacas/radioterapia , Linfoma de Células T/radioterapia , Recidiva Local de Neoplasia/radioterapia , Doses de Radiação , Irradiação Corporal Total , Idoso , Seguimentos , Fidelidade a Diretrizes , Humanos , Masculino , Reirradiação , Medição de Risco , Telemetria
3.
Am J Physiol Lung Cell Mol Physiol ; 308(5): L464-78, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25539853

RESUMO

Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice.


Assuntos
Elastina/metabolismo , Matriz Extracelular/metabolismo , Haploinsuficiência , Pulmão/patologia , Respiração Artificial , Remodelação Vascular , Animais , Animais Recém-Nascidos , Antígenos CD/metabolismo , Apoptose , Caderinas/metabolismo , Feminino , Immunoblotting , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/irrigação sanguínea , Pulmão/enzimologia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/patologia , Microvasos/fisiopatologia , Elastase Pancreática/metabolismo , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/fisiopatologia
4.
Pulm Pharmacol Ther ; 28(1): 25-34, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24140177

RESUMO

BACKGROUND: 18:1/18:1-Dioleoyl-phosphatidylgycerol (DOPG) is a surfactant phospholipid that is nearly non-detectable in neonatal surfactant films. When alveolar macrophages are exposed to DOPG in vitro, secretory phospholipase A2 (sPLA2) production is blocked, resulting in suppressed macrophage activity and improved surfactant function. We investigated whether the addition of DOPG to a commercially available surfactant preparation would improve lung function in a neonatal piglet model of acute respiratory distress syndrome. MATERIALS AND METHODS: Respiratory failure was achieved by triple-hit lung injury (repeated broncho-alveolar lavage, injurious ventilation, tracheal lipopolysaccharide instillation, each intervention 24 h apart) in twenty-four domestic piglets aged 2-6 days and subject to mechanical ventilation. Following each lung injury protocol the piglets were treated with surfactant alone or with surfactant + DOPG. RESULTS: Within 72 h of mechanical ventilation, we observed significantly improved gas exchange (oxygenation and ventilation), lung mechanics (compliance and resistance of the respiratory system), and pulmonary oedema (extra-vascular lung water index) in the surfactant + DOPG group. This favourable clinical effect could be attributed to improved surfactant function, reduced sPLA2 secretion, inhibition of macrophage migration, reduced alveolar epithelial apoptosis, and suppression of amphiregulin and TGF-ß1 expression in pulmonary tissues as a prerequisite for fibrous lung repair. CONCLUSIONS: We conclude that surfactant fortified by DOPG preserves lung function, and prevents alveolar epithelial injury and fibrous stimulus by reduction of sPLA2 in a neonatal model of acute respiratory distress syndrome without any relevant discernable side effects. Hence, DOPG supplementation in a neonatal lung exerts important function protecting effects and seems to be justified in cases of overwhelming pulmonary inflammation.


Assuntos
Apoptose/efeitos dos fármacos , Fosfatidilgliceróis/farmacologia , Surfactantes Pulmonares/farmacologia , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Edema Pulmonar/prevenção & controle , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Respiração Artificial , Suínos
5.
Am J Respir Cell Mol Biol ; 47(2): 158-69, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22403805

RESUMO

D-myo-inositol-1,2,6-trisphosphate (IP3) is an isomer of the naturally occurring second messenger D-myo-inositol-1,4,5-trisphosphate, and exerts anti-inflammatory and antiedematous effects in the lung. Myo-inositol (Inos) is a component of IP3, and is thought to play an important role in the prevention of neonatal pulmonary diseases such as bronchopulmonary dysplasia and neonatal acute lung injury (nALI). Inflammatory lung diseases are characterized by augmented acid sphingomyelinase (aSMase) activity leading to ceramide production, a pathway that promotes increased vascular permeability, apoptosis, and surfactant alterations. A novel, clinically relevant triple-hit model of nALI was developed, consisting of repeated airway lavage, injurious ventilation, and lipopolysaccharide instillation into the airways, every 24 hours. Thirty-five piglets were randomized to one of four treatment protocols: control (no intervention), surfactant alone, surfactant + Inos, and surfactant + IP3. After 72 hours of mechanical ventilation, lungs were excised from the thorax for subsequent analyses. Clinically, oxygenation and ventilation improved, and extravascular lung water decreased significantly with the S + IP3 intervention. In pulmonary tissue, we observed decreased aSMase activity and ceramide concentrations, decreased caspase-8 concentrations, reduced alveolar epithelial apoptosis, the reduced expression of interleukin-6, transforming growth factor-ß1, and amphiregulin (an epithelial growth factor), reduced migration of blood-borne cells and particularly of CD14(+)/18(+) cells (macrophages) into the airspaces, and lower surfactant surface tensions in S + IP3-treated but not in S + Inos-treated piglets. We conclude that the admixture of IP3 to surfactant, but not of Inos, improves gas exchange and edema in our nALI model by the suppression of the governing enzyme aSMase, and that this treatment deserves clinical evaluation.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Fosfatos de Inositol/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Edema Pulmonar/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Anfirregulina , Animais , Animais Recém-Nascidos , Líquido da Lavagem Broncoalveolar , Caspase 8/metabolismo , Ceramidas/metabolismo , Modelos Animais de Doenças , Feminino , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Linfotoxina-alfa/metabolismo , Masculino , Alvéolos Pulmonares/metabolismo , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Surfactantes Pulmonares/metabolismo , Surfactantes Pulmonares/farmacologia , Respiração Artificial/métodos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Esfingomielina Fosfodiesterase/metabolismo , Tensão Superficial/efeitos dos fármacos , Suínos
6.
J Cell Mol Med ; 16(11): 2813-26, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22882773

RESUMO

Hypoxemic respiratory failure of the neonatal organism involves increased acid sphingomyelinase (aSMase) activity and production of ceramide, a second messenger of a pro-inflammatory pathway that promotes increased vascular permeability, surfactant alterations and alveolar epithelial apoptosis. We comparatively assessed the benefits of topical aSMase inhibition by either imipramine (Imi) or phosphatidylinositol-3,5-bisphosphate (PIP2) when administered into the airways together with surfactant (S) for fortification. In this translational study, a triple-hit acute lung injury model was used that entails repeated airway lavage, injurious ventilation and tracheal lipopolysaccharide instillation in newborn piglets subject to mechanical ventilation for 72 hrs. After randomization, we administered an air bolus (control), S, S+Imi, or S+PIP2. Only in the latter two groups we observed significantly improved oxygenation and ventilation, dynamic compliance and pulmonary oedema. S+Imi caused systemic aSMase suppression and ceramide reduction, whereas the S+PIP2 effect remained compartmentalized in the airways because of the molecule's bulky structure. The surfactant surface tensions improved by S+Imi and S+PIP2 interventions, but only to a minor extent by S alone. S+PIP2 inhibited the migration of monocyte-derived macrophages and granulocytes into airways by the reduction of CD14/CD18 expression on cell membranes and the expression of epidermal growth factors (amphiregulin and TGF-ß1) and interleukin-6 as pro-fibrotic factors. Finally we observed reduced alveolar epithelial apoptosis, which was most apparent in S+PIP2 lungs. Exogenous surfactant "fortified" by PIP2, a naturally occurring surfactant component, improves lung function by topical suppression of aSMase, providing a potential treatment concept for neonates with hypoxemic respiratory failure.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Fosfatos de Fosfatidilinositol/administração & dosagem , Lesão Pulmonar Aguda/patologia , Administração Tópica , Anfirregulina , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/citologia , Antígenos CD18/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Ceramidas/metabolismo , Modelos Animais de Doenças , Feminino , Glicoproteínas/metabolismo , Imipramina/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Surfactantes Pulmonares , Respiração Artificial , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Suínos , Fator de Crescimento Transformador beta/metabolismo
7.
Drug Metab Pharmacokinet ; 31(2): 146-55, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26948953

RESUMO

Elafin is a potent reversible inhibitor of the pro-inflammatory proteases leukocyte elastase and protease 3. It is currently in clinical development for the use in postoperative inflammatory diseases. We investigated the pharmacokinetics of (99m)Tc-labeled elafin ((99m)Tc-Elafin) in blood and individual organs in rat after bolus intravenous injection using the single photon emission tomography (SPECT). (99m)Tc-Elafin predominantly accumulated in the kidney reaching a maximum of 8.5% ± 0.1% of the injected dose per gram (ID/g) at 5 min post injection (p.i) and decreased only slowly during 24 h. In contrast, the initially high radio activity recorded in the other organs rapidly decreased parallel to the radioactivity detected in blood. The blood kinetics fits to a two compartment kinetics model. The radio activity in the dissected kidney was 4.98 ± 1.24%ID/g 24 h p.i, while in other organs, including the brain, no accumulation of (99m)Tc-Elafin was detected. At this time point 30% of the detected radioactivity in the kidney was identified to be not metabolized (99m)Tc-Elafin. In conclusion, the blood and organ-specific kinetic data provide a basis for planning of adequate dosing regimens and the high accumulation of intact elafin in the kidney favors clinical developments targeting inflammatory kidney diseases, such as chronic allograft nephropathy after kidney transplantation.


Assuntos
Elafina/farmacocinética , Inibidores Enzimáticos/farmacocinética , Tecnécio/química , Animais , Elafina/química , Elafina/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Ratos , Distribuição Tecidual
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