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1.
Nat Commun ; 10(1): 4241, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534124

RESUMO

Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8+T cells with anti-CD8ß antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8+T cells into PbA-infected TCRß-/- mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8+T cells in an IFNγ-dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.


Assuntos
Lesão Pulmonar Aguda/patologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Interferon gama/imunologia , Malária/imunologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/parasitologia , Animais , Modelos Animais de Doenças , Células Endoteliais/imunologia , Feminino , Pulmão/parasitologia , Pulmão/patologia , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/imunologia , Edema Pulmonar/parasitologia , Edema Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/parasitologia
2.
J Agric Food Chem ; 67(28): 7855-7868, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31274310

RESUMO

Bee pollen (BP) collected from different floras possesses various potential bioactivities, but the mechanism-related research on anti-inflammatory effects is limited. Here, three types of BP originating from Camellia sinensis L. (BP-Cs), Nelumbo nucifera Gaertn. (BP-Nn), and Brassica campestris L. (BP-Bc) were assessed using molecular and metabolomics methods to determine their anti-inflammatory effects. The differences in polyphenolic abundance of three types of BP extracts were determined by HPLC-DAD/Q-TOF-MS. In vitro anti-inflammatory effects of three BP extracts were evaluated in a lipopolysaccharide (LPS)-induced RAW 264.7 cells model. BP-Cs extract with the most abundant polyphenols was found to be the most effective in reducing inflammation by downregulating inflammatory-related genes expression and blocking the activation of MAPK and NF-κB signaling pathways. Polyphenol-rich BP-Cs was further evaluated for their in vivo anti-inflammatory effect in a LPS-induced acute lung injury mouse model. An UPLC-Q-TOF/MS-based metabolomics approach was applied to analyze metabolite changes in mouse serum. Weshowed that the pretreated BP-Cs extract alleviated inflammation and regulated glycerophospholipid metabolism significantly. Our findings provide a foundation for developing and justifying BP as a potential anti-inflammatory ingredient in functional foods or nutraceutical formulations.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Extratos Vegetais/administração & dosagem , Pólen/química , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/química , Abelhas , Brassica/química , Camellia sinensis/química , Cromatografia Líquida de Alta Pressão , Humanos , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos ICR , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Nelumbo/química , Extratos Vegetais/química , Polifenóis/administração & dosagem , Polifenóis/química , Células RAW 264.7
3.
Int Immunopharmacol ; 73: 568-574, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203114

RESUMO

PIM kinase is involved in the cellular processes of growth, differentiation and apoptosis. However, the role of PIM1 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains largely unknown. A trend of PIM1 in the lung tissue of LPS-induced ALI at different time points was detected. Histology, wet/dry (W/D) ratio, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and survival rate analyses were performed when mice received the PIM1 inhibitor SMI-4a intratracheally 3 h before LPS administration. Cytokine production in vivo and in vitro was measured after SMI-4a pretreatment. NF-κB subunit p65 expression in nuclei and phosphorylation at Ser276 in lung tissues or cells were detected by Western blot analysis. The results showed that PIM1 mRNA and protein were upregulated in the lung tissue of LPS-induced ALI. The PIM1 inhibitor SMI-4a markedly improved the survival rate after lethal LPS administration, reduced the severity of lung edema, attenuated the histologic injuries of the lung tissue and reduced the counts of infiltrated inflammatory cells in the BALF. The PIM1 inhibitor SMI-4a suppressed the production of cytokines in LPS-treated RAW264.7 cell supernatants and BALF. Furthermore, LPS administration upregulated the levels of nuclear p65 and phosphorylated p65 (p-p65) at Ser276, whereas pretreatment with the PIM1 inhibitor SMI-4a reduced p65 upregulation in the nucleus and p-p65 at Ser276. Taken together, these data indicate that the PIM1 inhibitor SMI-4a may serve as a promising therapeutic strategy for LPS-induced ALI by suppressing macrophage production of cytokines via a reduction of p65 activities.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Compostos de Benzilideno/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tiazolidinedionas/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Compostos de Benzilideno/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Tiazolidinedionas/farmacologia , Fator de Transcrição RelA/imunologia
4.
Int J Mol Med ; 44(2): 617-629, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173158

RESUMO

Classical dendritic cells (cDCs) are involved in the pathogenesis of inflammatory lung diseases; however, their contributions in acute respiratory distress syndrome (ARDS), which is pathophysiologically inflammatory, remain unknown. The present study aimed to explore the regulatory effects of pulmonary cDCs on acute lung inflammation and injury in lipopolysaccharide (LPS)­induced ARDS. Fms­like tyrosine kinase 3­ligand (FLT3L) and lestaurtinib, a specific activator and an inhibitor of FLT3 signaling respectively, were used separately for the pretreatment of C57BL/6 mice for 5 consecutive days. ARDS was induced by intratracheal injection of LPS, and mice were sacrificed 6 and 24 h later. Flow cytometry was used to measure the aggregation and maturation of pulmonary cDCs. The ratio of lung wet weight to body weight (LWW/BW) and histopathological analyses were assessed to evaluate lung edema and lung injury. Tumor necrosis factor­α and interleukin (IL)­6 levels were measured by ELISA to evaluate acute lung inflammation. The levels of interferon­Î³, IL­1ß, IL­4 and IL­10, and the expression of the transcription factors T­box­expressed­in­T­cells (T­bet) and GATA binding protein 3, were quantified by ELISA, RT­qPCR and western blotting to evaluate the balance of the Th1/Th2 response. Myeloperoxidase (MPO) activity was measured to evaluate neutrophil infiltration. The results demonstrated that the aggregation and maturation of pulmonary cDCs reached a peak at 6 h after LPS challenge, followed by a significant decrease at 24 h. FLT3L pretreatment further stimulated the aggregation and maturation of pulmonary cDCs, resulting in elevated lung MPO activity and increased T­bet expression, which in turn led to aggravated LWW/BW, acute lung inflammation and injury. However, lestaurtinib pretreatment inhibited the aggregation and maturation of pulmonary cDCs, decreased lung MPO activity and T­bet expression, and eventually improved LWW/BW, acute lung inflammation and injury. The present results suggested that pulmonary cDCs regulated acute lung inflammation and injury in LPS­induced ARDS through the modulation of neutrophil infiltration and balance of the Th1/Th2 response.


Assuntos
Lesão Pulmonar Aguda/imunologia , Células Dendríticas/imunologia , Pneumonia/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Células Dendríticas/patologia , Modelos Animais de Doenças , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/patologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Tirosina Quinase 3 Semelhante a fms/imunologia
5.
Int J Mol Med ; 44(2): 479-490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173183

RESUMO

Acute lung injury (ALI) is a critical syndrome that is associated with a high morbidity and mortality in patients. Sevoflurane has a lung protective effect in ALI as it reportedly has anti­inflammatory and apoptotic­regulating activity. However, the mechanism is still not entirely understood. The aim of the present study was to explore the effects of sevoflurane on lipopolysaccharide (LPS)­induced ALI in mice and the possible mechanisms involved. The results revealed that sevoflurane treatment improved LPS­induced lung injury, as evidenced by the reduction in mortality, lung permeability, lung wet/dry ratio and lung histopathological changes in mice. Total cell counts and the production of pro­inflammatory cytokines [tumor necrosis factor­α, interleukin (IL)­1ß and IL­6] in bronchoalveolar fluid were also decreased following treatment with sevoflurane. Additionally, LPS­triggered apoptosis in lung tissues, which was eliminated by sevoflurane. Furthermore, a miRCURY™ LNA array was employed to screen for differentially expressed microRNAs (miRs/miRNAs). Among these miRNAs, 6 were differentially expressed and were involved in the inflammatory response, but only miR­27a­3p (miR­27a) was regulated by sevoflurane. Subsequently, the present study investigated whether sevoflurane exerts its function through the modulation of miR­27a. The results demonstrated that the overexpression of miR­27a via an injection with agomiR­27a produced similar protections as sevoflurane, while the inhibition of miR­27a suppressed the lung protective effects of sevoflurane in ALI mice. In addition, the present study identified that miR­27a inhibited Toll­like receptor 4 (TLR4) by binding to its 3'­untranslated region. Western blot analysis demonstrated that sevoflurane may ameliorate the inflammatory response by blocking the miR­27a/TLR4/MyD88/NF­κB signaling pathway. The present results indicate that sevoflurane may be a viable therapeutic option in the treatment of patients with ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , MicroRNAs/imunologia , NF-kappa B/imunologia , Sevoflurano/uso terapêutico , Receptor 4 Toll-Like/imunologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Lipopolissacarídeos/imunologia , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Fator 88 de Diferenciação Mieloide/imunologia , Sevoflurano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Inflamm Res ; 68(8): 665-675, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147742

RESUMO

OBJECTIVES: Cytokines participate in the progression of acute respiratory distress syndrome (ARDS), and uncontrolled inflammation is a central issue of acute lung injury (ALI). Interleukin (IL)-33 is a nuclear protein that has been reported to have a proinflammatory role in ARDS. Studies have shown that excessive autophagy may lead to the increased mortality of patients with ARDS, while several investigations indicated that IL-33 and autophagy interact with one another. The present study sought to clarify the relation between autophagy and IL-33's proinflammatory role in ARDS. METHODS: We built a lipopolysaccharide (LPS)-induced lung injury mouse model. To study the relationship between IL-33 and autophagy, mice were pretreated with rapamycin (RAPA; a promoter of autophagy) and 3-methyladenine (3-MA; an inhibitor of autophagy) prior to LPS administration. The expression of IL-33 in serum and bronchoalveolar lavage fluid (BALF) was measured. Immunohistochemistry of IL-33 in lung tissue was examined. Th1,Th2 cytokines/chemokine levels in serum and BALF were tested. Further, the severity of lung injury was evaluated. And the nuclear factor-kappa B (NF-κB)'s nuclear translocation in lung tissue was detected. RESULTS: In comparison with the control group, the levels of IL-33 in serum and BALF were increased after LPS injection. Th1 cytokines/chemokine levels were significantly increased in serum and BALF, while Th2 cytokine levels changed only a little. The levels of IL-33 in serum and BALF of the RAPA group was significantly increased after LPS was injected as compared with the LPS group; additionally, the levels of IL-33 in serum and BALF of the 3-MA group was significantly reduced after LPS was injected as compared with the LPS group, and that lung injury was ameliorated after 3-MA pretreatment. Th1 cytokines and chemokines in both serum and BALF were also decreased in the 3-MA group. Furthermore, we found that the nuclear translocation of NF-κB increased after LPS administration, and NF-κB's nuclear translocation was significantly increased in comparison with the LPS group after RAPA pretreatment. In contrast, NF-κB's nuclear translocation decreased after 3-MA pretreatment as compared with the LPS group. CONCLUSIONS: These findings showed that autophagy might regulate IL-33 by activating or inhibiting NF-κB to control the uncontrolled inflammation of acute lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , Autofagia , Citocinas/imunologia , NF-kappa B/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/induzido quimicamente , Adulto , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Lipopolissacarídeos , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL
7.
Int Immunopharmacol ; 74: 105658, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177016

RESUMO

The acute respiratory distress syndrome (ARDS), a devastating clinical syndrome, is one of the most severe complications of acute lung injury (ALI). Despite of decades of clinical trials and supportive ventilation strategies, the incidence and mortality of ALI/ARDS remain high. DL-3-n-butylphthalide (NBP) is a synthesized raceme of L-3-n-butylphthalide which has been approved to possess various activities. In the current study, we aimed to investigate the effect of NBP on ALI in lipopolysaccharide (LPS)-treated mice. We found that 10 mg/kg and 50 mg/kg NBP significantly prevented LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. Sirtuin 1 (SIRT1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was increased by NBP in lung of LPS-treated mice. Knockout of SIRT1 significantly aggravated LPS-induced ALI. Moreover, the absence of SIRT1 notably inhibited NBP-induced protective effects against LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. However, knockout of SIRT1 did not completely inhibit NBP-induced upregulation of Nrf2 and attenuation of ALI. The results demonstrated that NBP could activate Nrf2 antioxidant signaling in a SIRT1-dependent and SIRT1-independent manner, resulting in the amelioration of oxidative stress, inflammation and pulmonary edema. The data highlights the importance of SIRT1/Nrf2 signaling in the protective effects of NBP.


Assuntos
Lesão Pulmonar Aguda/imunologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Fator 2 Relacionado a NF-E2/imunologia , Sirtuína 1/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Benzofuranos/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/imunologia , Edema Pulmonar/patologia , Sirtuína 1/genética
8.
Inhal Toxicol ; 31(3): 107-118, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31039646

RESUMO

Objective: To establish a rat model with respiratory and pulmonary responses caused by inhalation exposure to non-lethal concentrations of ammonia (NH3) that can be used for evaluation of new medical countermeasure strategies for NH3-induced acute lung injury (ALI). This is of great value since no specific antidotes of NH3-induced injuries exist and medical management relies on supportive and symptomatically relieving efforts. Methods: Female Sprague-Dawley rats (8-9 weeks old, 213g ± 2g) were exposed to NH3 using two different exposure regimens; nose-only inhalation or intratracheal instillation. The experiment was terminated 5 h, 24 h, 14 and 28 days post-exposure. Results: Nose-only inhalation of NH3 (9000-15 000 ppm) resulted in increased salivation and labored breathing directly post-exposure. Exposure did not increase inflammatory cells in bronchoalveolar lavage fluid but exposure to 12 000 ppm NH3 during 15 min reduced body weight and induced coagulation abnormalities by increasing serum fibrinogen levels. All animals were relatively recovered by 24 h. Intratracheal instillation of NH3 (1%) caused early symptoms of ALI including airway hyperresponsiveness, neutrophilic lung inflammation and altered levels of coagulation factors (increased fibrinogen and PAI-1) and early biomarkers of ALI (IL-18, MMP-9, TGFß) which was followed by increased deposition of newly produced collagen 14 days later. Histopathology analysis at 5 h revealed epithelial desquamation and that most lesions were healed after 14 days. Conclusions: This study demonstrates that intratracheal instillation can reproduce several early hallmarks of ALI. Our findings therefore support that the intratracheal instillation exposure regimen can be used for new medical countermeasure strategies for NH3-induced ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Amônia/administração & dosagem , Amônia/toxicidade , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Colágeno/metabolismo , Feminino , Fibrina/metabolismo , Fibrinogênio/análise , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/fisiopatologia , Nariz , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Traqueia
9.
Int Immunopharmacol ; 73: 312-320, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129418

RESUMO

Progressive lung injury and pulmonary inflammation can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). Interleukin-1ß (IL-1ß) is a key pro-inflammatory cytokine that can further exaggerate inflammation, which is cleaved and activated by the NALP3 inflammasome. Although the nuclear receptor Rev-erbα attenuates the level of LPS-induced pulmonary inflammation, the mechanism remains unclear. In this study, we investigated the influence of LPS-induced production of IL-1ß and Rev-erbα on the development of lung inflammation. Herein, we demonstrate that Rev-erbα reduces IL-1ß production and lung injury following an intraperitoneal injection of LPS, which is dependent on the NF-κB/NALP3 pathway. Thus, Rev-erbα is able to decrease the extent of acute lung injury by regulating IL-1ß production. This mechanism may represent a potential novel therapeutic approach for lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Glicina/análogos & derivados , Glicina/farmacologia , Interleucina-1beta/imunologia , Isoquinolinas/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células RAW 264.7 , Transdução de Sinais , Tiofenos/farmacologia
10.
Environ Sci Pollut Res Int ; 26(18): 18465-18469, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31044379

RESUMO

Our study investigated the ameliorative effects of thymoquinone (TQ) on the pulmonary blood vessels which were injured after intratracheal administration of Escherichia coli-derived lipopolysaccharide (LPS) in a rat model. Forty rats (150 ± 50 g) were randomly divided into four groups equally. The first group was intratracheally administered LPS (Escherichia coli O55:B5) at a dose 200 µg. The second group was co-administered intraperitoneal injection of TQ and LPS daily for one week. The third group was provided intraperitoneal injection of 1 mg of TQ. The fourth group was administered normal saline intratracheally at the rate of 200 µl. The results revealed that cytokine level of interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNFα) in serum was reduced in TQ-treated rats. Immunohistochemical study showed that expression of NF-kB was countered in the lung tissue by the application of TQ. In addition, the lesion score for various pathological aberrations were checked when rats were treated with TQ. From the results of the present study, it was concluded that TQ has an ameliorative effect on the pulmonary blood vascular damage via rearrangement of the cytokines in response to LPS injury in the rat model.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Benzoquinonas/farmacologia , Citocinas/sangue , Lipopolissacarídeos/toxicidade , Pulmão/irrigação sanguínea , Microvasos/efeitos dos fármacos , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/imunologia , Animais , Regulação para Baixo/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Microvasos/imunologia , Microvasos/patologia , NF-kappa B/genética , Ratos , Ratos Wistar
11.
Inhal Toxicol ; 31(2): 52-60, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31068039

RESUMO

Objective: We have previously found that mesenchymal stem cell (MSC) therapy can ameliorate phosgene-induced acute lung injury (ALI). Moreover, exosomes can be used as a cell-free alternative therapy. In the present study, we aimed to assess the effect of MSC-derived exosomes on phosgene-induced ALI. Methods: MSC-derived exosomes were isolated from MSCs through ultracentrifugation. Sprague-Dawley (SD) rats were exposed to phosgene at 8.33 g/m3 for 5 min. MSC-derived exosomes were intratracheally administered and rats were sacrificed at the time points of 6, 24 and 48 h. Results: Compared with the phosgene group, MSC-derived exosomes reversed respiratory function alterations, showing increased levels of TV, PIF, PEF and EF50 as well as decreased levels of RI and EEP. Furthermore, MSC-derived exosomes improved pathological alterations and reduced wet-to-dry ratio and total protein content in BALF. MSC-derived exosomes reduced the levels of TNF-α, IL-1ß and IL-6 and increased the IL-10 level in BALF and plasma. MSC-derived exosomes suppressed the MMP-9 level and increased the SP-C level. Conclusions: MSC-derived exosomes exerted beneficial effects on phosgene-induced ALI via modulating inflammation, inhibiting MMP-9 synthesis and elevating SP-C level.


Assuntos
Lesão Pulmonar Aguda/terapia , Substâncias para a Guerra Química/toxicidade , Exossomos/transplante , Pulmão/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Fosgênio/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Peptídeos/genética , Ratos Sprague-Dawley , Testes de Função Respiratória , Regulação para Cima
12.
Mol Immunol ; 112: 51-58, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078116

RESUMO

Particulate matter (PM)2.5 is a common air pollutant known to induce damages in the respiratory, cardiovascular, and nervous systems. Previous study has shown that acute and high-level PM insult could significantly aggravate the severity of LPS-induced acute lung injury (ALI). However, humans typically experience more chronic and low-level PM, of which the effect on ALI is yet unclear. Here, we varied the concentration of PM from low, medium, to high, which was given to mice via intratracheal instillation for a short period of time. Compared to the saline-treated mice, mice with medium or high PM treatment presented significantly higher mortality rate, weight reduction, and bronchoalveolar lavage (BAL) protein concentration during ALI, while mice with low PM treatment did not demonstrate significant differences from saline-treated mice. However, when the PM was given for an elongated period of time, PM, even at the low level, significantly aggravated ALI severity. Furthermore, the PM-mediated changes were sustained even after PM withdrawal. We also examined the CD4 T cells in saline- or PM-treated mice. We found that, although PM did not significantly change the number of lung-infiltrating CD4 T cells, it significantly altered the composition of lung-infiltrating CD4 T cells, characterized by having a higher T-bet/Foxp3 ratio in the PM-treated group compared to the saline-treated group. Additionally, the Treg-mediated suppression was reduced in PM-treated mice. The effect of PM on CD4 T cells depended on the concentration of PM and the duration of the treatment, and was independent of the PM withdrawal. Overall, these results demonstrated that chronic and low-level PM was sufficient at aggravating ALI and altering pulmonary CD4 T cells, and the effect could be sustained even after PM withdrawal.


Assuntos
Lesão Pulmonar Aguda/imunologia , Linfócitos T CD4-Positivos/imunologia , Pulmão/imunologia , Material Particulado/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/imunologia
13.
Int Immunopharmacol ; 72: 275-283, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005037

RESUMO

Candida albicans infection-induced acute lung injury is one of the most prevalent diseases in immunosuppressive individual. Nevertheless, the mechanism by which Candida albicans induced acute lung injury remains unclear. The present study investigated the mechanism by which Candida albicans induced acute lung injury in mice. Mice were randomly divided into four groups and intratracheally injected with 60 µl Candida albicans (106 CFU) or normal saline. Half of the mice were sacrificed at 6 h after Candida albicans. The rest of the mice for survival test were observed until 7 d after Candida albicans. As expected, immunosuppression aggravated Candida albicans-induced acute lung injury and death in mice. Additionally, Candida albicans infection elevated mRNA levels of pro-inflammatory and chemokines in lungs and the levels of IL-6, IL-1ß and IL-17 in serum. Further study showed that Candida albicans promoted nuclear translocation of NF-κB p50 and p65 subunits in pulmonary epithelial cells and interstitial cells. Candida albicans induced pulmonary p38, ERK1/2 and Akt phosphorylation in normal and immunosuppressive mice. Moreover, Candida albicans infection activated pulmonary STAT3 signaling in normal and immunosuppressive mice. Overall, these results suggest that Candida albicans induced acute lung injury and death may be through activating several inflammatory signaling pathways.


Assuntos
Lesão Pulmonar Aguda/imunologia , Candidíase/imunologia , Imunossupressão , Lesão Pulmonar Aguda/etiologia , Animais , Candida albicans , Candidíase/complicações , Ciclofosfamida , Citocinas/sangue , Dexametasona , Inflamação/imunologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais
14.
Int Immunopharmacol ; 72: 21-30, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30959368

RESUMO

Although the protective effects of genipin against acute lung injury (ALI) have been described previously, the associated mechanism remains unclear. We have previously reported that genipin exerts its pharmacological effects by regulating autophagy. Here, we hypothesized that the up-regulation of autophagy may contribute to the protective effects exhibited by genipin against ALI. In the present study, ALI was induced by intratracheal LPS administration in rats. Genipin treatment significantly reduced LPS-induced lung injury as evidenced by improved histopathology, decreased lung edema, total cells, and protein concentration in the bronchoalveolar lavage fluid (BALF). This protection was inhibited by 3-methyladenine (3-MA), an inhibitor of autophagy. Genipin treatment reduced the expression of P62 and increased the expression of Beclin-1 and LC3II, indicating increased autophagy. Genipin treatment also alleviated LPS-induced cell apoptosis (down-regulation of Bax, up-regulation of Bcl-2, and decreased number of terminal deoxynucleotidyl transferase dUTP nick end label-positive cells) and oxidative stress (increased SOD and decreased MDA content) in the lung. Furthermore, genipin attenuated LPS-induced production of TNF-α, IL-1ß, and IL-6 in the lung and BALF. These protective effects induced by genipin were reversed by 3-MA treatment, indicating that autophagy was involved in the protective effects exerted by genipin against inflammation and apoptosis in ALI. In A549 cells incubated with LPS for 6 h, genipin treatment increased the number of GFP-LC3 punctae. 3-MA prevented the protective effects of genipin against mitochondrial dysfunction and cell death. These findings suggest that genipin protects against apoptosis and inflammation in LPS-induced ALI by promoting autophagy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Iridoides/uso terapêutico , Substâncias Protetoras/uso terapêutico , Células A549 , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Autofagia/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/imunologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Humanos , Iridoides/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley
15.
Int Immunopharmacol ; 72: 243-251, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31003001

RESUMO

Paraquat (PQ), a highly toxic herbicide, selectively accumulates in the lungs and causes pulmonary damage through oxidative and inflammatory processes after intentional or accidental poisoning. The resulting acute lung injury (ALI) is characterized by neutrophil infiltration and extensive inflammation with rapid respiratory failure. However, effective therapies are lacking. We tested the hypothesis that suppressing neutrophil-derived matrix metalloproteinase 9 (MMP9) would ameliorate the inflammatory milieu and alleviate PQ-induced ALI. Lung injury was assessed in mice intratracheally injected with PQ aerosol by measuring the lung static compliance, cell count and neutrophil percentage of the bronchoalveolar lavage fluid (BALF) and lung, alveolar-capillary permeability, and histopathological lung injury scores. MMP9/2 activity was assessed by gelatin zymography, and the location of neutrophils and MMP9 in the lung was evaluated by immunofluorescence costaining. In the neutrophil depletion experiment, mice received anti-Ly6G antibody intraperitoneally; for the MMP inhibition experiment, an MMP inhibitor, doxycycline (DOX), was administered by gavage. In PQ-induced ALI, the activity of neutrophil-derived MMP9 but not MMP2 increased significantly. Neutrophil depletion reduced the inflammatory burden, improved pulmonary edema, and reduced the PQ-induced overexpression of MMP9. Consistently, oral delivery of DOX to mice decreased the overexpression of MMP9 that was activated by PQ and phenocopied the resolution of PQ-induced ALI observed after neutrophil depletion. Taken together, our results show for the first time that DOX is involved in the resolution of PQ-induced ALI via a mechanism involving reducing the activity of neutrophil-derived MMP9. We speculate that DOX may represent a novel therapeutic strategy for PQ-induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Metaloproteinase 9 da Matriz/imunologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/química , Herbicidas , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Paraquat , Peroxidase/imunologia
16.
Int Immunopharmacol ; 72: 467-472, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31035089

RESUMO

Bacterial pneumonia is a leading cause of death in the animal husbandry. Acute lung injury (ALI), most often seen as a part of systemic inflammatory process, characterized by progressive hypoxemia, edema, and neutrophil accumulation in the lung. Baicalin has been reported to inhibit inflammatory response, but its role in ALI remains unknown. The purpose of our study was to determine the protective effect and possible mechanism of baicalin against avian pathogenic Escherichia coli (APEC)-induced ALI in chicken. Chickens were conditioned with baicalin 1 week before intratracheally instilled with APEC. Then, chickens were sacrificed by CO2 inhalation 12 h later and the lung tissues were collected for examining histopathological changes, wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, levels of pro-inflammatory cytokines and activation of NF-κB signaling pathway. The results showed that pre-treatment of chickens with baicalin significantly alleviated the death rate, histopathological changes in lung tissues. The W/D ratio, MPO activity and production of cytokines, such as IL-1ß, TNF-α, IL-6 of lung tissues were also decreased following treatment with baicalin. Furthermore, the mechanism responsible for these effects was attributed to the inhibitory effect of baicalin on nuclear factor-κB (NF-κB) signaling activation. These data thus support the application of baicalin as a potential medicine for the treatment of E. coli-induced ALI by regulating NF-κB signaling pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Infecções por Escherichia coli/tratamento farmacológico , Flavonoides/uso terapêutico , NF-kappa B/imunologia , Doenças das Aves Domésticas/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/veterinária , Animais , Galinhas , Citocinas/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/veterinária , Flavonoides/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/patologia , Transdução de Sinais/efeitos dos fármacos
17.
Kaohsiung J Med Sci ; 35(5): 265-276, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31001923

RESUMO

The pathogenesis of acute lung injury (ALI) is characterized by lung inflammation and lung oxidative stress. The study was conducted in order to investigate the effect toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) exhibited on oxidative stress in ALI. After the rats had been assigned into different groups, arterial blood, white blood cell (WBC), lung permeability index (LPI), wet/dry (W/D) ratio, TLR4 and NF-κB expression and superoxide dismutase (SOD), myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) were examined. Afterward, the correlation between the levels of TLR4 and NF-κB was determined. Decreased levels of PaO2 , SOD, MPO, and GSH accompanied by increased levels of PaCO2 , WBC number, LPI and W/D ratio, MDA and ROS, as well as TLR4 and NF-κB expressions in the ALI, ALI + NF-κB inhibitor, and ALI + phosphate buffer saline groups were found. Inhibition of NF-κB resulted in increased PaO2 and decreased PaCO2 levels, WBC number, and LPI and W/D ratio. Decreased expression of NF-κB increased SOD, GSH, and MPO, but decreased MDA and ROS. We also found that NF-κB inhibition resulted in the improvement of ALI in rats. TLR4 and NF-κB expressions were negatively correlated with levels of SOD, MPO, and GSH, and positively correlated with MDA and ROS levels. In summary, our findings provided evidence that inhibition of the TLR4/NF-κB signaling pathway decreases oxidative stress, thereby improving ALI. As a result, NF-κB signaling pathway has shown potential as a therapeutic target in ALI therapy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , NF-kappa B/imunologia , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Receptor 4 Toll-Like/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Animais , Regulação da Expressão Gênica , Glutationa/agonistas , Glutationa/imunologia , Glutationa/metabolismo , Lipopolissacarídeos/administração & dosagem , Malondialdeído/antagonistas & inibidores , Malondialdeído/imunologia , Malondialdeído/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/genética , Peroxidase/imunologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética
18.
J Ethnopharmacol ; 242: 111713, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30703491

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Eriobotrya japonica, a traditional herbal medicine in China and Japan, has long been used to treat chronic bronchitis and coughs. AIM OF THE STUDY: Pentacyclic triterpenoids (PTs), especially ursolic acid (UA), have been found as reversibly and competitively human neutrophil elastase (HNE) inhibitors. However, the limited solubility and poor bioavailability of PTs hinder their clinical use. Crude plant extracts may have a greater activity than isolated constituents of the equivalent dosage. In this study, an Eriobotrya japonica (loquat leaves) extract (triterpenoid composition of loquat leaves, TCLL) with enriched PTs such as UA was prepared. The study aims to compare the HNE inhibitory (HNEI) effect in vitro and the therapeutic effect on acute lung injury (ALI) in vivo between TCLL and UA. MATERIALS AND METHODS: An HNEI activity bioassay was performed with Sivelestat sodium hydrate as a positive control. A lipopolysaccharide (LPS)-induced lung inflammatory model was established to evaluate TCLL's therapeutic effect on ALI in vivo. The absorption of UA in TCLL and in UA alone was determined using a Caco-2 cell uptake model and LC-MS. RESULTS: The IC50 values of TCLL and UA for the HNEI effect were 3.26 ±â€¯0.56 µg/mL and 8.49 ±â€¯0.42 µg/mL (P < 0.01), respectively. TCLL significantly improved the inflammatory cells and inflammatory cytokine production in mice compared with the LPS group (P < 0.05). Additionally, it performed better than the UA alone group (P < 0.05). Moreover, the uptake by Caco-2 cells of UA in TCLL was higher than that in UA alone (P < 0.05). CONCLUSION: TCLL has a significant HNEI effect in vitro and a therapeutic effect on LPS-induced inflammation in a mouse model. Both the effects are more efficient than UA. Improved absorption of PTs in TCLL may be one explanation for these results.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Eriobotrya , Elastase de Leucócito/antagonistas & inibidores , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células CACO-2 , Citocinas/imunologia , Humanos , Contagem de Leucócitos , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Folhas de Planta
19.
Transfusion ; 59(3): 1090-1101, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30784079

RESUMO

BACKGROUND: Acute lung injury (ALI) is a severe complication of transfusion. In a previous study, we saw that inhibition of the CD40/CD40L complex allowed restoration of ALI lesions in an experimental mouse model. OBJECTIVES: This study focused on pancreas-associated injury development during experimental ALI pathogenesis and its limitation through CD40/CD40L complex inhibition. MATERIALS AND METHODS: An ALI mouse model was established through intraperitoneal lipopolysaccharide and intravenous anti-major histocompatibility complex class I monoclonal antibody injection. Preemption of lesions was achieved with intravenous injection of neutralizing anti-CD40L monoclonal antibody 30 minutes before the trigger, that is, anti-major histocompatibility complex class I monoclonal antibody administration. Histology and immunoassay analyses were used to evaluate pancreatic lesions. RESULTS: ALI development induced significant degradation of the lungs and pancreas and was associated with pancreatic lesions. Different scores were established showing more severe injury to the pancreas in ALI conditions; however, injury was significantly reduced through CD40/CD40L complex inhibition. CONCLUSION: This study supports the idea that several organs are exposed during ALI development, and particularly when such experimental ALI aims at mimicking transfusion-associated ALI; nevertheless, preventive treatment inhibiting CD40/CD40L (sCD40L) complex formation provides protection from lung disease as well as disease of other organs.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Pâncreas/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Animais , Antígenos CD40/imunologia , Ligante de CD40/imunologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pâncreas/imunologia
20.
Biochem Biophys Res Commun ; 511(1): 49-56, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30760405

RESUMO

Acute lung injury (ALI) is served as a severe life-threatening disease. However, the pathogenesis that contributes to ALI has not been fully understood. Tumor necrosis factor receptor-associated factor 1 (TRAF1) interacts with multiple regulators, performing its diverse role in biological functions. However, the effects of TRAF1 on ALI remain unknown. In this study, we attempted to explore the role of TRAF1 in ALI progression. The findings suggested that TRAF1-knockout (KO) markedly attenuated LPS-induced severe mortality rate in murine animals. LPS-elicited histological alterations in pulmonary tissues were significantly alleviated by TRAF1-deletion. Additionally, TRAF1 knockout effectively attenuated lung injury, as evidenced by the reduced lung wet/dry (W/D) weight ratio, as well as decreased bronchoalveolar lavage fluid (BALF) protein levels and neutrophil infiltration. Meanwhile, TRAF1 deletion markedly lessened inflammation, oxidative stress and apoptosis in BALF and/or lung tissues. The levels of pro-inflammatory cytokines stimulated by LPS were down-regulated by TRAF1 ablation, along with the inactivation of nuclear factor κB (NF-κB). LPS-promoted reactive oxygen species (ROS) generation was decreased in TRAF1-KO mice, partly through the improvement of anti-oxidants. Apoptosis was also inhibited by TRAF1 deletion in lung tissues of LPS-challenged mice through the suppression of cleaved Caspase-3. Moreover, TRAF1 knockout significantly decreased c-Jun N-terminal kinase (JNK) activation and its down-streaming signal of c-Jun in pulmonary samples of LPS-induced mice. Importantly, the in vitro study suggested that promoting JNK activation markedly abrogated TRAF1 knockdown-attenuated inflammation, ROS production and apoptosis in LPS-exposed A549 cells. Therefore, our experimental results provided evidence that TRAF1 suppression effectively protected LPS-induced ALI against inflammation, oxidative stress and apoptosis through the suppression of JNK activity.


Assuntos
Lesão Pulmonar Aguda/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Lipopolissacarídeos/imunologia , Fator 1 Associado a Receptor de TNF/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Linhagem Celular , Ativação Enzimática , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL
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