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1.
Inflammopharmacology ; 32(1): 603-627, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37847473

RESUMO

BACKGROUND: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30-40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. METHODS: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. RESULTS: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA-approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. CONCLUSION: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm.


Assuntos
Lesão Pulmonar Aguda , COVID-19 , Síndrome do Desconforto Respiratório , Humanos , NF-kappa B , Lipopolissacarídeos/farmacologia , Cloridrato de Olopatadina , Síndrome da Liberação de Citocina , Transdução de Sinais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Proteínas I-kappa B , Citocinas
2.
Front Cell Infect Microbiol ; 13: 1194495, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37674577

RESUMO

Background: The transcriptomic studies targeting circular RNAs (circRNAs) in bronchoalveolar lavage fluid (BALF) exosomes of acute respiratory distress syndrome (ARDS) patients caused by severe pneumonia have rarely been reported. This study aimed to screen and validate abnormally expressed circRNAs in exosomes from BALF of patients with ARDS caused by severe pneumonia and then evaluate the diagnostic values of these circRNAs for ARDS. Method: BALF was collected from four patients with ARDS caused by severe pneumonia and four healthy subjects. CircRNA expression profile was obtained by microarray analysis in BALF exosomes of the discovery cohort. The differentially expressed circRNAs in BALF exosomes were verified by real-time quantitative PCR (RT-qPCR) and underwent competitive endogenous RNA (ceRNA) network construction and functional enrichment analysis. Results: A total of 629 circRNAs were differentially expressed in BALF exosomes between ARDS patients and healthy subjects. Nine differentially expressed circRNAs were validated by RT-qPCR, and seven were consistent with the results of microarray analysis. CeRNA network analysis was performed for hsa_circRNA_002809, hsa_circRNA_042882, and hsa_circRNA_104034. Functional enrichment analysis showed that the target genes were mainly associated with hypoxia-induced damage, inflammatory response, and the HIF-1 signaling pathway. Hsa_circRNA_042882 and hsa_circRNA_104034 can be regarded as promising diagnostic biomarkers for patients with ARDS caused by severe pneumonia, with remarkable sensitivity and specificity of the area under the curve of 0.8050 and 1 or 0.835 and 0.799, respectively. Conclusion: This study obtained circRNA expression profiles of ARDS patients, and hsa_circRNA_042882 and hsa_circRNA_104034 were regarded as promising diagnostic biomarkers for patients with ARDS caused by severe pneumonia.


Assuntos
Exossomos , Pneumonia , Síndrome do Desconforto Respiratório , Humanos , RNA Circular , Líquido da Lavagem Broncoalveolar , Pneumonia/diagnóstico , Síndrome do Desconforto Respiratório/diagnóstico , Biomarcadores
3.
Respir Res ; 23(1): 366, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36539808

RESUMO

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating respiratory disorder with high rates of mortality and morbidity, but the detailed underlying mechanisms of ALI/ARDS remain largely unknown. Mechanosensitive ion channels (MSCs), including epithelial sodium channel (ENaC), Piezo channels, transient receptor potential channels (TRPs), and two-pore domain potassium ion (K2P) channels, are highly expressed in lung tissues, and the activity of these MSCs can be modulated by mechanical forces (e.g., mechanical ventilation) and other stimuli (e.g., LPS, hyperoxia). Dysfunction of MSCs has been found in various types of ALI/ARDS, and MSCs play a key role in regulating alveolar fluid clearance, alveolar epithelial/endothelial barrier function, the inflammatory response and surfactant secretion in ALI/ARDS lungs. Targeting MSCs exerts therapeutic effects in the treatment of ALI/ARDS. In this review, we summarize the structure and functions of several well-recognized MSCs, the role of MSCs in the pathogenesis of ALI/ARDS and recent advances in the pharmacological and molecular modulation of MSCs in the treatment of ALI/ARDS. According to the current literature, targeting MSCs might be a very promising therapeutic approach against ALI/ARDS.


Assuntos
Lesão Pulmonar Aguda , Surfactantes Pulmonares , Síndrome do Desconforto Respiratório , Humanos , Lesão Pulmonar Aguda/patologia , Síndrome do Desconforto Respiratório/terapia , Pulmão , Transdução de Sinais
4.
Front Immunol ; 13: 820718, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547731

RESUMO

The etiology of acute lung injury (ALI) is not clear, and the treatment of ALI presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of ALI and to define the target gene of Tanreqing (TRQ), which is a traditional Chinese medicine formula composed of five medicines, scutellaria baicalensis, bear bile powder, goat horn powder, honeysuckle and forsythia. Macrophage activation plays a critical role in many pathophysiological processes, such as inflammation. Although the regulation of macrophage activation has been extensively investigated, there is little knowledge of the role of long noncoding RNAs (lncRNAs) in this process. In this study, we found that lncRNA-SNHG1 expression is distinctly regulated in differently activated macrophages in that it is upregulated in LPS. LncRNA-SNHG1 knockdown attenuates LPS-induced M1 macrophage activation. The SNHG1 promoter was bound by NF-κB subunit p65, indicative of SNHG1 being a direct transcriptional target of LPS-induced NF-κB activation. SNHG1 acts as a proinflammatory driver that leads to the production of inflammatory cytokines and the activation of macrophages and cytokine storms by physically interacting with high-mobility group box 1 (HMGB1) in ALI. TRQ inhibited NF-κB signaling activation and binding of NF-κB to the SNHG1 promoter. In conclusion, this study defined TRQ target genes, which can be further elucidated as mechanism(s) of TRQ action, and provides insight into the molecular pathogenesis of ALI. The lncRNA-SNHG1/HMGB1 axis is an ideal therapeutic for ALI treatment.


Assuntos
Lesão Pulmonar Aguda , Proteína HMGB1 , RNA Longo não Codificante , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Medicamentos de Ervas Chinesas , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/genética , NF-kappa B/metabolismo , Pós , RNA Longo não Codificante/genética
5.
Acta Pharm Sin B ; 12(2): 600-620, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34401226

RESUMO

The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The properties such as clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the translation of siRNA is restricted by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

6.
Acta Pharmaceutica Sinica B ; (6): 600-620, 2022.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-929273

RESUMO

The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The properties such as clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the translation of siRNA is restricted by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

7.
J Inflamm (Lond) ; 17(1): 34, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33292269

RESUMO

BACKGROUND: Neutrophils rapidly respond to and clear infection from tissues, but can also induce tissue damage through excessive degranulation, when acute inflammation proceeds unchecked. A number of key neutrophil functions, including adhesion-dependent degranulation, are controlled by src family kinases. Dasatinib is a potent src inhibitor used in treating patients with chronic myeloid leukaemia and treatment-resistant acute lymphoblastic leukaemia. We hypothesized that dasatinib would attenuate acute inflammation by inhibiting neutrophil recruitment, degranulation and endothelial cell injury, without impairing bacterial clearance, in a murine model of bacteria-induced acute lung injury. C57BL/6 mice received intratracheal Escherichia coli, and were treated with intraperitoneal dasatinib or control. Bacterial clearance, lung injury, and markers of neutrophil recruitment and degranulation were measured. Separately, human blood neutrophils were exposed to dasatinib or control, and the effects on a range of neutrophil functions assessed. RESULTS: Dasatinib was associated with a dose-dependent significant increase in E. coli in the mouse lung, accompanied by impairment of organ function, reflected in significantly increased protein leak across the alveolar-capillary membrane. However, the number of neutrophils entering the lung was unaffected, suggesting that dasatinib impairs neutrophil function independent of migration. Dasatinib did not cause direct toxicity to human neutrophils, but led to significant reductions in phagocytosis of E. coli, adhesion, chemotaxis, generation of superoxide anion and degranulation of primary and secondary granules. However, no biologically important effect of dasatinib on neutrophil degranulation was observed in mice. CONCLUSIONS: Contrary to our starting hypothesis, src kinase inhibition with dasatinib had a detrimental effect on bacterial clearance in the mouse lung and therefore does not represent an attractive therapeutic strategy to treat primary infective lung inflammation. Data from human neutrophils suggest that dasatanib has inhibitory effects on a range of neutrophil functions.

8.
J Clin Pharm Ther ; 45(6): 1515-1519, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32860252

RESUMO

WHAT IS KNOWN AND OBJECTIVE: This article summarizes the effects of sivelestat on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) or ARDS with coagulopathy, both of which are frequently seen in patients with COVID-19. COMMENT: COVID-19 patients are more susceptible to thromboembolic events, including disseminated intravascular coagulation (DIC). Various studies have emphasized the role of neutrophil elastase (NE) in the development of DIC in patients with ARDS and sepsis. It has been shown that NE inhibition by sivelestat mitigates ALI through amelioration of injuries in alveolar epithelium and vascular endothelium, as well as reversing the neutrophil-mediated increased vascular permeability. WHAT IS NEW AND CONCLUSIONS: Sivelestat, a selective NE inhibitor, has not been evaluated for its possible therapeutic effects against SARS-CoV-2 infection. Based on its promising beneficial effects in underlying complications of COVID-19, sivelestat could be considered as a promising modality for better management of COVID-19-induced ALI/ARDS or coagulopathy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Tratamento Farmacológico da COVID-19 , Coagulação Intravascular Disseminada/tratamento farmacológico , Glicina/análogos & derivados , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Sulfonamidas/uso terapêutico , Lesão Pulmonar Aguda/etiologia , COVID-19/complicações , Coagulação Intravascular Disseminada/etiologia , Glicina/uso terapêutico , Humanos , Síndrome do Desconforto Respiratório/etiologia , Resultado do Tratamento
9.
Int J Mol Sci ; 21(15)2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32731491

RESUMO

Pseudomonas aeruginosa is an important opportunistic pathogen responsible for the cause of acute lung injury and acute respiratory distress syndrome. P. aeruginosa isthe leading species isolated from patients with nosocomial infection and is detected in almost all the patients with long term ventilation in critical care units. P. aeruginosa infection is also the leading cause of deleterious chronic lung infections in patients suffering from cystic fibrosis as well as the major reason for morbidity in people with chronic obstructive pulmonary disease. P. aeruginosa infections are linked to diseases with high mortality rates and are challenging for treatment, for which no effective remedies have been developed. Massive lung epithelial cell death is a hallmark of severe acute lung injury and acute respiratory distress syndrome caused by P. aeruginosa infection. Lung epithelial cell death poses serious challenges to air barrier and structural integrity that may lead to edema, cytokine secretion, inflammatory infiltration, and hypoxia. Here we review different types of cell death caused by P. aeruginosa serving as a starting point for the diseases it is responsible for causing. We also review the different mechanisms of cell death and potential therapeutics in countering the serious challenges presented by this deadly bacterium.


Assuntos
Lesão Pulmonar Aguda , Células Epiteliais , Pulmão , Infecções por Pseudomonas , Pseudomonas aeruginosa , Síndrome do Desconforto Respiratório , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Morte Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/microbiologia , Síndrome do Desconforto Respiratório/patologia
10.
Int J Mol Sci ; 21(14)2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32650621

RESUMO

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30-40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Enzimas Desubiquitinantes/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Animais , Humanos , Pneumonia/metabolismo , Transdução de Sinais/fisiologia , Ubiquitina/metabolismo , Ubiquitinação/fisiologia
11.
Ann Transl Med ; 7(19): 508, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31728361

RESUMO

Acute respiratory distress syndrome (ARDS) is a complex entity with high potential for harm and healthcare resource utilization. Despite multiple clinical advances in its ventilatory management, ARDS continues to be one of the most challenging disease processes for intensivists. It continues to lack a direct, proven and desperately needed effective therapeutic intervention. Given their biologic rationale, corticosteroids have been widely used by clinicians and considered useful by many in the management of ARDS since its first description. Adult data is abundant, yet contradictory. Controversy remains regarding the routine use of corticosteroids in ARDS. Therefore, widespread evidence-based recommendations for this heterogeneous disease process have not been made. In this article, our aim was to provide a summary of available evidence for the role of steroids in the treatment of ARDS, while giving special focus on pediatric ARDS (PARDS).

12.
J Clin Med ; 8(9)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470655

RESUMO

Increasing evidence suggests the potential role of extracellular vesicles (EVs) in many lung diseases. According to their subcellular origin, secretion mechanism, and size, EVs are currently classified into three subpopulations: exosomes, microvesicles, and apoptotic bodies. Exosomes are released in most biofluids, including airway fluids, and play a key role in intercellular communication via the delivery of their cargo (e.g., microRNAs (miRNAs)) to target cell. In a physiological context, lung exosomes present protective effects against stress signals which allow them to participate in the maintenance of lung homeostasis. The presence of air pollution alters the composition of lung exosomes (dysregulation of exosomal miRNAs) and their homeostatic property. Indeed, besides their potential as diagnostic biomarkers for lung diseases, lung exosomes are functional units capable of dysregulating numerous pathophysiological processes (including inflammation or fibrosis), resulting in the promotion of lung disease progression. Here, we review recent studies on the known and potential role of lung exosomes/exosomal miRNAs, in the maintaining of lung homeostasis on one hand, and in promoting lung disease progression on the other. We will also discuss using exosomes as prognostic/diagnostic biomarkers as well as therapeutic tools for lung diseases.

13.
Eur J Trauma Emerg Surg ; 45(4): 671-679, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29627883

RESUMO

PURPOSE: While damage control resuscitation is known to confer a survival advantage in severely injured patients, high-ratio blood component therapy should be initiated only in carefully selected trauma patients, due to the morbidity associated with blood product use. With this project, we aim to identify the effect of platelet transfusion in non-massively transfused bluntly injured patients. METHODS: The Glue Grant database was retrospectively queried and severely injured blunt trauma patients who underwent non-massive transfusion were identified. Patients were divided into quartiles depending on platelet volume they were transfused in the first 48 h. Outcomes of interest included mortality; ventilator, Intensive Care Unit (ICU) and hospital length of stay (LOS); infectious and non-infectious complications. Multivariable regression models were fitted for these outcomes, controlling for age, pre-existing comorbidities, injury severity, acute physiologic derangement, neurologic injury burden, and other fluid and blood product resuscitation. RESULTS: There was no difference in mortality, LOS, or the incidence of multi-organ failure and infectious complications. However, patients receiving ≥ 250 mL of platelets were more likely to develop acute respiratory distress syndrome (ARDS) compared to those who received < 250 mL [odds ratio 1.91 (95% CI 1.10-3.33, p = 0.022)]. CONCLUSIONS: Pre-emptive platelet transfusion should be avoided in non-massively transfused blunt injury victims in the absence of true or functional thrombocytopenia, as it increases risk for ARDS with no survival benefit.


Assuntos
Transfusão de Plaquetas/efeitos adversos , Síndrome do Desconforto Respiratório/etiologia , Ferimentos não Penetrantes/terapia , Adulto , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Transfusão de Plaquetas/mortalidade , Estudos Prospectivos , Síndrome do Desconforto Respiratório/mortalidade , Fatores de Risco , Ferimentos não Penetrantes/mortalidade
14.
Mol Immunol ; 99: 134-144, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29783158

RESUMO

Acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by its acute onset, diffuse alveolar damage, intractable hypoxemia, and non-cardiogenic pulmonary edema. Acute lung injury(ALI) can trigger persistent lung inflammation and fibrosis through activation of the NLRP3 inflammasome and subsequent secretion of mature IL-1ß, suggesting that the NLRP3 inflammasome is a potential therapeutic target for ALI, for which new therapeutic approaches are needed. Our present study aims to assess whether pirfenidone,with anti-fibrotic and anti-inflammatory properties, can improve LPS-induced inflammation and fibrosis by inhibiting NLRP3 inflammasome activation. Male C57BL/6 J mice were intratracheally injected with LPS to induce ALI. Mice were administered pirfenidone by oral gavage throughout the entire experimental course. The mouse macrophage cell line (J774 A.1) was incubated with LPS and ATP, with or without PFD pre-treatment. We demonstrated that PFD remarkably ameliorated LPS-induced pulmonary inflammation and fibrosis and reduced IL-1ß and TGF-ß1 levels in bronchoalveolar lavage fluid(BALF). Pirfenidone substantially reduced NLRP3 and ASC expression and inhibited caspase-1 activation and IL-1ß maturation in lung tissues. In vitro, the experiments revealed that PFD significantly suppressed LPS/ATP-induced production of reactive oxygen species (ROS) and decreased caspase-1 activation and the level of IL-1ß in J774 A.1 cells. Taken together, the administration of PFD reduced LPS-induced lung inflammation and fibrosis by blocking NLRP3 inflammasome activation and subsequent IL-1ß secretion. These findings indicated that PFD can down-regulate NLRP3 inflammasome activation and that it may offer a promising therapeutic approach for ARDS patients.


Assuntos
Fibrose/tratamento farmacológico , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Piridonas/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Caspase 1/metabolismo , Linhagem Celular , Fibrose/induzido quimicamente , Fibrose/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
15.
Am J Physiol Lung Cell Mol Physiol ; 312(2): L231-L242, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27913426

RESUMO

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an important cause of mortality in critically ill patients. Macrophages play an important role in the pathogenesis of ALI/ARDS. To investigate the role and underlying mechanisms of circulating monocytes and resident alveolar macrophages (AMs) in ALI/ARDS, we depleted circulating monocytes and AMs by clodronate-loaded liposome (CL) in a lipopolysaccharide (LPS)-induced ALI/ARDS mouse model. Our results indicated that depletion of circulating monocytes by intravenous injection of CL 2 days before intratracheal LPS treatment significantly suppressed the acute lung injury in mice with ALI/ARDS, accompanied with significant reduction in neutrophil influx, interleukin-17, monocyte chemoattractant protein 1, high-mobility group box 1 protein, suppressor of cytokine signaling 3, and surfactant protein D (SP-D) in the lungs of 2 days intratracheal LPS-treated mice. In contrast, depletion of AMs by intratracheal delivery of CL enhanced the acute lung injury in association with upregulation of these mediators. Blocking monocyte chemoattractant protein 1 signaling by intraperitoneal instillation of anti-mouse CCL2 neutralizing antibody significantly reduced acute lung injury and neutrophil influx. In addition, SP-D was upregulated by mediators released from AMs because primary murine type II alveolar epithelial cells expressed more SP-D after treatment with bronchoalveolar lavage from LPS-treated mice or the conditioned media from LPS-treated RAW 264.7 cells. The results indicated that circulating monocytes are proinflammatory, but AMs have anti-inflammatory functions in the early phase of ALI/ARDS. The study provided a molecular basis for the treatment of ALI/ARDS through modulation of circulating monocytes and AMs.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proteína HMGB1/metabolismo , Interleucina-17/metabolismo , Monócitos/metabolismo , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/metabolismo , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Feminino , Lipopolissacarídeos , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Proteína D Associada a Surfactante Pulmonar/metabolismo , Transdução de Sinais , Células Th17/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
16.
Respir Med ; 117: 27-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27492510

RESUMO

BACKGROUND AND OBJECTIVE: We hypothesized that increased pulmonary vascular permeability may play a role in the pathogenesis of an acute exacerbation of the idiopathic interstitial pneumonias (AE-IIPs). Angiopoietin-2 (Ang-2) promotes endothelial activation, destabilization, and inflammation. The purpose of this study was to examine whether Ang-2 expression was associated with the pathogenesis of AE-IIPs. METHODS: Twenty-three patients with AE-IIP patients, 18 acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, 37 idiopathic pulmonary fibrosis (IPF) patients, and 33 healthy volunteers (HVs) were enrolled. The serum level of Ang-2 was measured by an enzyme-linked immunosorbent assay. RESULTS: The serum levels of Ang-2 were higher in AE-IIPs and ALI/ARDS patients than in IPF patients and HVs; the BALF levels of Ang-2 were also higher than in IPF patients. There was a positive correlation between the serum level of Ang-2 and the CRP in patients with AE-IIP patients, whereas a significant positive correlation was found between the serum Ang-2 level and the CRP or SOFA scores of the ALI/ARDS patients. Although the baseline Ang-2 level was not related to survival, the Ang-2 levels significantly declined in survivors during treatment, while they did not change in non-survivors. CONCLUSIONS: Increased pulmonary vascular permeability and inflammation due to Ang-2 may play a role in the pathogenesis of AE-IIPs.


Assuntos
Lesão Pulmonar Aguda/sangue , Angiopoietina-2/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Pulmão/metabolismo , Síndrome do Desconforto Respiratório/sangue , Lesão Pulmonar Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Permeabilidade Capilar/genética , Progressão da Doença , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Inflamação/metabolismo , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/fisiopatologia , Estudos Retrospectivos , Análise de Sobrevida , Tomógrafos Computadorizados
17.
Biomed Hub ; 1(3)2016.
Artigo em Inglês | MEDLINE | ID: mdl-28503550

RESUMO

Surfactant protein (SP)-B is a 79-residue polypeptide crucial for the biophysical and physiological function of endogenous lung surfactant. SP-B is a member of the Saposin or Saposin-like proteins (SAPLIP) family of proteins that share an overall three-dimensional folding pattern based on secondary structures and disulfide connectivity and exhibit a wide diversity of biological functions. Here we review the synthesis, molecular biophysics and activity of synthetic analogs of Saposin proteins designed to mimic those interactions of the parent proteins with lipids that enhance interfacial activity. Saposin proteins generally interact with target lipids as either monomers or multimers via well-defined amphipathic helices, flexible hinge domains, and insertion sequences. Based on the known 3D-structural motif for the Saposin family, we show how bioengineering techniques may be used to develop minimal peptide constructs that maintain desirable structural properties and activities in biomedical applications. One important application is the molecular design, synthesis and activity of Saposin mimics based on the SP-B structure. Synthetic lung surfactants containing active SP-B analogs may be potentially useful in treating diseases of surfactant deficiency or dysfunction including the neonatal respiratory distress syndrome and acute lung injury/acute respiratory distress syndrome.

18.
Int J Exp Pathol ; 96(3): 133-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25664386

RESUMO

The aim of this study was to determine the effects of previous administration of metyrapone (met) on the acute lung injury (ALI) induced by caecal ligation and puncture (CLP) and to explore met's relationship with endogenous glucocorticoids (GCs) as measured by inflammatory, oxidative and functional parameters. One hundred and thirty-five Wistar rats were divided into three main groups: Control (Naïve), Sham and CLP. The animals received pretreatment one hour before surgery. The Naïve group did not undergo any procedure or pretreatment. The Sham group only had the caecum exposed and was pretreated with saline. The CLP group was divided into three pretreatments: metyrapone (CLP met 50 mg/kg i.p.), dexamethasone (CLP dex 0.5 mg/kg i.p.) or saline (CLP sal equivalent volume of 0.9% NaCl). Analyses were performed after 6 and 24 h of sepsis. Previous administration of met significantly increased inflammatory cells, as well as myeloperoxidase (MPO) activity in the lung tissue and alveolar collapsed area, with consequent impairment of respiratory mechanics being observed compared to Sham and Naïve; CLP sal exhibited similar results to those of met. The met reduced corticosterone (CCT) levels and dramatically increased hydrogen peroxide (H2 O2 ) levels in the lung tissue compared to CLP sal. Our results suggest that previous administration of met may have contributed to increased pulmonary oxidative stress and increased mortality by mechanisms dependent of endogenous GC.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Corticosterona/biossíntese , Inibidores Enzimáticos/toxicidade , Pulmão/efeitos dos fármacos , Metirapona/toxicidade , Choque Séptico/complicações , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Corticosterona/sangue , Modelos Animais de Doenças , Regulação para Baixo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Mecânica Respiratória/efeitos dos fármacos , Esteroide 11-beta-Hidroxilase/metabolismo , Fatores de Tempo
19.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-465388

RESUMO

Objective To investigate the effects of early continuous renal replacement thempy(CRRT)on acute lung injury and prognosis in severe acute pancreatitis (SAP)patients.Methods 46 SAP patients were divided into the two groups randomly:the control group and CRRT treatment group.The levels of IL-1β,IL-6,TNF-α,the APACHEⅡscore,oxygenation index,the incidence of acute lung injury(ALI)/acute respiratory distress syndrome (ARDS),ICU stay were compared between the two groups.Results The level of interleukin-6(IL-6)in the con-trol group was significantly higher than that in CRRT group in day 1(t=2.265,P0.05).Conclusion Early CRRT therapy can eliminate the IL-1β,IL-6 and TNF-αin SAP patients,which can improve the oxygenation index and reduce the incidences of ALI/ARDS,may provide more clinical benefits in the early phase of SAP.

20.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-490428

RESUMO

Objective To investigate the impact of relevant factors in mechanical ventilation on intraabdominal pressure in patients with ALI/ARDS by continuous monitoring of intra-abdominal pressure.Methods A total of 116 ALI/ARDS patients treated with mechanical ventilation in ICU were enrolled in this study.Intra-abdominal pressure (IAP) was recorded continuously.Meanwhile ventilator parameters, arterial blood gas analysis, hemodynamic variables, and as well as the levels of IL-4, IL-8 and TNF-α in blood and bronchial alveolar lavage fluid (BALF) were determined and recorded.The detection of risk factors for intra-abdomen hypertension (IAH) were carried out using multivariate stepwise logistic regression.ROC curve analysis used to estimate the diagnostic performance of these parameters for IAH.Results The oxygenation index (PaO2/FiO2) in patients with IAH after 2 hours' mechanical ventilation was significantly lower than that in patients with normal intra-abdomen pressure (IAP) (P < 0.01);PEEP and RR in mechanical ventilation were higher in IAH group (P < 0.01 or P =0.001);Mean artery pressure (MAP), ejection time percent (ET), stroke volume (SV), cardiac index (CI) were lower in IAH group than those in normal IAP group (P < 0.01);the levels of IL-4, IL-8 and TNF-α in blood and bronchial alveolar lavage fluid were higher in IAH group than those in normal IAP group (P < 0.01);IAH patients have a higher mortality on 28 d (Log rank test, P =0.023).Poor oxygenation index (PaO2/ FiO2) after 2 hours' ventilation, high PEEP setting, low MAP, ET, SV, CI and elevated IL-4 in the BALF were resulted in increasing risk of IAH for ARDS patients under mechanical ventilation support.Conclusions The monitoring of intra-abdominal pressure should be emphasized for ALI/ARDS patients when mechanical ventilation was employed.PaO2/FiO2, SV and IL-4 in BALF might be the independent risk factors of IAH.

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