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1.
Crit Care Med ; 47(11): e911-e918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31567350

RESUMO

OBJECTIVES: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. DESIGN: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. SETTING: Research laboratory. SUBJECTS: Wild-type, TRPV4-deficient C57BL/6J mice, 8-10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. INTERVENTION: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. MEASUREMENTS AND MAIN RESULTS: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4 mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated CONCLUSIONS:: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

3.
Sci Transl Med ; 10(456)2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158154

RESUMO

The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may result in clinically relevant alveolar damage. We report that mechanical ventilation in mice increased the expression of Lamin-A, a major determinant of nuclear membrane stiffness, in alveolar epithelial cells. Lamin-A expression increased and nuclear membrane compliance decreased in human bronchial epithelial cells after a mechanical stretch stimulus and in a murine model of lung injury after positive-pressure ventilation. Reducing Lamin-A maturation by depletion of the protease-encoding gene Zmpste24 preserved alveolar nuclear membrane compliance after mechanical ventilation in mice. Ventilator-induced proapoptotic gene expression changes and lung injury were reduced in mice lacking Zmpste24 compared to wild-type control animals. Similarly, treatment with the human immunodeficiency virus protease inhibitors lopinavir and ritonavir reduced the accumulation of Lamin-A at nuclear membranes and preserved nuclear membrane compliance after mechanical ventilation, mimicking the protective phenotype of Zmpste24-/- animals. These results show that the pathophysiological response to lung mechanical stretch is sensed by the nuclear membranes of lung alveolar cells, and suggest that protease inhibitors might be effective in preventing ventilator-induced lung injury.


Assuntos
Células Epiteliais Alveolares/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Mecanotransdução Celular , Membrana Nuclear/metabolismo , Respiração Artificial/efeitos adversos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/ultraestrutura , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Humanos , Laminas/metabolismo , Lopinavir/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/ultraestrutura , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Metaloendopeptidases/deficiência , Metaloendopeptidases/metabolismo , Camundongos Endogâmicos C57BL , Membrana Nuclear/efeitos dos fármacos , Membrana Nuclear/ultraestrutura , Ritonavir/farmacologia
4.
Am J Respir Cell Mol Biol ; 59(3): 289-294, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29708395

RESUMO

Neutrophils are key players in acute lung injury. Once recruited from the circulation, these cells release cytotoxic molecules that lead to tissue disruption, so their blockade has been advocated to prevent lung damage. However, lung injury also occurs during neutropenia and usually involves a very poor outcome. There is emerging evidence that neutrophils not only contribute to that early damage but also orchestrate later repair. Neutrophils promote epithelial proliferation and are a source of proteases, which are required for the processing of the collagen scar and facilitation of cell migration. This article reviews the effects of neutrophils in repair after acute lung injury, focusing on their role as biovectors for proteases and other molecules involved in tissue remodeling.


Assuntos
Lesão Pulmonar/terapia , Pulmão/patologia , Metaloproteinases da Matriz/metabolismo , Doença Aguda , Animais , Humanos , Modelos Animais
5.
Ann Transl Med ; 6(2): 28, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29430445

RESUMO

Cell migration is a core process to preserve homeostasis. Release of chemotactic signals induces changes in cell cytoskeleton to facilitate migration. This includes the rearrangement of cytoskeleton, genomic reprogramming and the modification of the surrounding extracellular matrix (ECM) to allow the motion of cells through. In the special case of repair after acute lung injury, cells must migrate while exposed to an increased mechanical stretch caused either by an increased work of breathing or positive-pressure ventilation. Interestingly, the cell response to this increased mechanical load can modify virtually all the mechanisms involved in cell migration. In this review we explore the interplay between stretch and the machinery responsible for cell migration. A translational approach to find new therapies in acute lung injury must take into account these interactions in order to develop effective treatments that promote lung repair.

6.
Thorax ; 73(4): 321-330, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28947666

RESUMO

BACKGROUND: Neutrophils may cause tissue disruption during migration and by releasing cytotoxic molecules. However, the benefits of neutrophil depletion observed in experimental models of lung injury do not correspond with the poor outcome of neutropenic patients. METHODS: To clarify the role of neutrophils during repair, mice with ventilator induced lung injury (VILI) were rendered neutropenic after damage, and followed for 48 hours of spontaneous breathing. Lungs were harvested and inflammatory mediators and matrix metalloproteinases measured. Bronchoalveolar lavage fluid (BALF) from ventilated patients with acute respiratory distress syndrome, with or without neutropenia, was collected, the same mediators measured and their effects in an ex vivo model of alveolar repair studied. Finally, neutropenic mice were treated after VILI with exogenous matrix metalloproteinase-9 (MMP-9). RESULTS: Lungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor α, interferon γ and macrophage inflammatory protein 2, and absence of MMP-9. BALF from ventilated neutropenic patients with acute respiratory distress syndrome showed similar results. BALFs from neutropenic patients yielded a delayed closure rate of epithelial wounds ex vivo, which was improved by removal of collagen or addition of exogenous MMP-9. Lastly, treatment of neutropenic mice with exogenous MMP-9 after VILI reduced tissue damage without modifying cytokine concentrations. CONCLUSION: Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.


Assuntos
Metaloproteinase 9 da Matriz/biossíntese , Neutropenia/metabolismo , Neutrófilos/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/citologia , Quimiocina CXCL2/metabolismo , Modelos Animais de Doenças , Humanos , Interferon gama/metabolismo , Camundongos , Neutropenia/patologia , Síndrome do Desconforto Respiratório do Adulto/enzimologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Fator de Necrose Tumoral alfa/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/enzimologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle
7.
J Mol Med (Berl) ; 95(5): 487-497, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28120021

RESUMO

ᅟ: Matrix metalloproteinases can modulate the inflammatory response through processing of cyto- and chemokines. Among them, MMP-14 is a non-dispensable collagenase responsible for the activation of other enzymes, triggering a proteolytic cascade. To identify the role of MMP-14 during the pro-inflammatory response, wildtype and Mmp14 -/- mice were challenged with lipopolysaccharide. MMP-14 levels decreased after endotoxemia. Mutant animals showed 100% mortality, compared to 50% in wildtype mice. The increased mortality was related to a more severe lung injury, an impaired lung MMP-2 activation, and increased levels of the alarmin S100A9. There were no differences in the expression of other mediators including Il6, Cxcl2, Tgfb, Il10, or S100a8. A similar result was observed in lung explants of both genotypes cultured in presence of lipopolysaccharide. In this ex vivo model, exogenous activated MMP-2 ameliorated the observed increase in alarmins. Samples from septic patients showed a decrease in serum MMP-14 and activated MMP-2 compared to non-septic critically ill patients. These results demonstrate that the MMP-14-MMP-2 axis is downregulated during sepsis, leading to a proinflammatory response involving S100A9 and a more severe lung injury. This anti-inflammatory role of MMP-14 could have a therapeutic value in sepsis. KEY MESSAGES: • MMP-14 levels decrease in lungs from endotoxemic mice and serum from septic patients. • Mmp14 -/- mice show increased lung injury and mortality following endotoxemia. • Absence of Mmp14 decreases activated MMP-2 and increases S100A9 levels in lung tissue. • MMP-14 ameliorates inflammation by promoting S100A9 cleavage by activated MMP-2.


Assuntos
Endotoxemia/enzimologia , Endotoxemia/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Endotoxemia/induzido quimicamente , Feminino , Genótipo , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/metabolismo , Camundongos , Camundongos Mutantes , Pessoa de Meia-Idade , Sepse/enzimologia , Sepse/metabolismo
8.
Minerva Anestesiol ; 82(7): 731-2, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27124309
9.
Crit Care Med ; 44(7): 1406-13, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26909503

RESUMO

OBJECTIVE: Acute respiratory failure in hematological patients is related to a high mortality. Noninvasive mechanical ventilation may benefit a subset of these patients, but the overall effect on mortality and the risks derived from its failure are unclear. Our objective was to review the impact of initial ventilatory strategy on mortality and the risks related to noninvasive mechanical ventilation failure in this group of patients. DATA SOURCES: Data sources, including PubMed and conference proceedings, were searched from the year 2000 to January 2015. STUDY SELECTION: We selected studies reporting mortality and the need for mechanical ventilation in hematological patients with acute respiratory failure. DATA EXTRACTION: Two trained reviewers independently conducted study selection, abstracted data, and assessed the risk of bias. Discrepancies between reviewers were resolved through discussion and consensus. The outcomes explored were all-cause mortality after mechanical ventilation and incidence of noninvasive mechanical ventilation failure. DATA SYNTHESIS: A random-effects model was used in all the analysis. Thirteen studies, involving 2,380 patients, were included. Use of noninvasive mechanical ventilation was related to a better outcome than initial intubation (risk ratio, 0.74; 95% CI, 0.65-0.84). Failure of noninvasive mechanical ventilation did not increase the overall risk of death (risk ratio, 1.02; 95% CI, 0.93-1.13). There were signs of publication bias and substantial heterogeneity among the studies. Compensation of this bias by using the trim-and-fill method showed a significant risk of death after noninvasive mechanical ventilation failure (risk ratio, 1.07; 95% CI, 1.00-1.14). Meta-regression analysis showed that the predicted risk of death for the noninvasive mechanical ventilation group acted as a significant moderator, with a higher risk of death after noninvasive mechanical ventilation failure in those studies reporting lower predicted mortality. CONCLUSIONS: Noninvasive mechanical ventilation is associated with a lower risk of death in hematological patients with respiratory failure. Noninvasive mechanical ventilation failure may worsen the prognosis, mainly in less severe patients.


Assuntos
Doenças Hematológicas/complicações , Respiração Artificial/métodos , Insuficiência Respiratória/terapia , Doença Aguda , Doenças Hematológicas/mortalidade , Humanos , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade
10.
Anesthesiology ; 124(2): 443-52, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26569171

RESUMO

BACKGROUND: Lung strain, defined as the ratio between end-inspiratory volume and functional residual capacity, is a marker of the mechanical load during ventilation. However, changes in lung volumes in response to pressures may occur in injured lungs and modify strain values. The objective of this study was to clarify the role of recruitment in strain measurements. METHODS: Six oleic acid-injured pigs were ventilated at positive end-expiratory pressure (PEEP) 0 and 10 cm H2O before and after a recruitment maneuver (PEEP = 20 cm H2O). Lung volumes were measured by helium dilution and inductance plethysmography. In addition, six patients with moderate-to-severe acute respiratory distress syndrome were ventilated with three strategies (peak inspiratory pressure/PEEP: 20/8, 32/8, and 32/20 cm H2O). Lung volumes were measured in computed tomography slices acquired at end-expiration and end-inspiration. From both series, recruited volume and lung strain (total, dynamic, and static) were computed. RESULTS: In the animal model, recruitment caused a significant decrease in dynamic strain (from [mean ± SD] 0.4 ± 0.12 to 0.25 ± 0.07, P < 0.01), while increasing the static component. In patients, total strain remained constant for the three ventilatory settings (0.35 ± 0.1, 0.37 ± 0.11, and 0.32 ± 0.1, respectively). Increases in tidal volume had no significant effects. Increasing PEEP constantly decreased dynamic strain (0.35 ± 0.1, 0.32 ± 0.1, and 0.04+0.03, P < 0.05) and increased static strain (0, 0.06 ± 0.06, and 0.28 ± 0.11, P < 0.05). The changes in dynamic and total strain among patients were correlated to the amount of recruited volume. An analysis restricted to the changes in normally aerated lung yielded similar results. CONCLUSION: Recruitment causes a shift from dynamic to static strain in early acute respiratory distress syndrome.


Assuntos
Pulmão/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Animais , Modelos Animais de Doenças , Pulmão/diagnóstico por imagem , Medidas de Volume Pulmonar , Masculino , Respiração com Pressão Positiva , Síndrome do Desconforto Respiratório do Adulto/terapia , Mecânica Respiratória , Volume de Ventilação Pulmonar , Tomografia Computadorizada por Raios X
11.
Am J Physiol Lung Cell Mol Physiol ; 309(8): L847-56, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26472813

RESUMO

Inflammation plays a key role in the development of ventilator-induced lung injury (VILI). Preconditioning with a previous exposure can damp the subsequent inflammatory response. Our objectives were to demonstrate that tolerance to VILI can be induced by previous low-pressure ventilation, and to identify the molecular mechanisms responsible for this phenomenon. Intact 8- to 12-wk-old male CD1 mice were preconditioned with 90 min of noninjurious ventilation [peak pressure 17 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O] and extubated. Seven days later, preconditioned mice and intact controls were submitted to injurious ventilation (peak pressure 20 cmH2O, PEEP 0 cmH2O) for 2 h to induce VILI. Preconditioned mice showed lower histological lung injury scores, bronchoalveolar lavage albumin content, and lung neutrophilic infiltration after injurious ventilation, with no differences in Il6 or Il10 expression. Microarray analyses revealed a downregulation of Calcb, Hspa1b, and Ccl3, three genes related to tolerance phenomena, in preconditioned animals. Among the previously identified genes, only Ccl3, which encodes the macrophage inflammatory protein 1 alpha (MIP-1α), showed significant differences between intact and preconditioned mice after high-pressure ventilation. In separate, nonconditioned animals, treatment with BX471, a specific blocker of CCR1 (the main receptor for MIP-1α), decreased lung damage and neutrophilic infiltration caused by high-pressure ventilation. We conclude that previous exposure to noninjurious ventilation induces a state of tolerance to VILI. Downregulation of the chemokine gene Ccl3 could be the mechanism responsible for this effect.


Assuntos
Quimiocina CCL3/genética , Respiração Artificial/efeitos adversos , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Animais , Regulação para Baixo , Tolerância Imunológica , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Respiração com Pressão Positiva/efeitos adversos , Receptores CCR1/antagonistas & inibidores , Lesão Pulmonar Induzida por Ventilação Mecânica/genética
12.
J Mol Med (Berl) ; 92(6): 665-76, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24535031

RESUMO

UNLABELLED: Autophagy has emerged as a key regulator of the inflammatory response. To examine the role of autophagy in the development of organ dysfunction during endotoxemia, wild-type and autophagy-deficient (Atg4b-null) mice were challenged with lipopolysaccharide. Animals lacking Atg4b showed increased mortality after endotoxemia. Among the different organs studied, only the lungs showed significant differences between genotypes, with increased damage in mutant animals. Autophagy was activated in lungs from wild-type, LPS-treated mice. Similarly, human bronchial cells show an increased autophagy when exposed to serum from septic patients. We found an increased inflammatory response (increased neutrophilic infiltration, higher levels of Il6, Il12p40, and Cxcl2) in the lungs from knockout mice and identified perinuclear sequestration of the anti-inflammatory transcription factor ATF3 as the putative mechanism responsible for the differences between genotypes. Finally, induction of autophagy by starvation before LPS exposure resulted in a dampened pulmonary response to LPS in wild-type, but not knockout, mice. Similar results were found in human bronchial cells exposed to LPS. Our results demonstrate the central role of autophagy in the regulation of the lung response to endotoxemia and sepsis and its potential modulation by nutrition. KEY MESSAGES: Endotoxemia and sepsis trigger autophagy in lung tissue. Defective autophagy increases mortality and lung inflammation after endotoxemia. Impairment of autophagy results is perinuclear ATF3 sequestration. Starvation ameliorates lung injury by an autophagy-dependent mechanism.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Autofagia/fisiologia , Endotoxemia/metabolismo , Endotoxemia/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Fator 3 Ativador da Transcrição/genética , Adulto , Idoso , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia , Linhagem Celular , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Endotoxemia/genética , Humanos , Lesão Pulmonar/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade
13.
Am J Respir Crit Care Med ; 188(6): 693-702, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23962032

RESUMO

RATIONALE: Critically ill patients frequently develop neuropsychological disturbances including acute delirium or memory impairment. The need for mechanical ventilation is a risk factor for these adverse events, but a mechanism that links lung stretch and brain injury has not been identified. OBJECTIVES: To identify the mechanisms that lead to brain dysfunction during mechanical ventilation. METHODS: Brains from mechanically ventilated mice were harvested, and signals of apoptosis and alterations in the Akt survival pathway were studied. These measurements were repeated in vagotomized or haloperidol-treated mice, and in animals intracerebroventricularly injected with selective dopamine-receptor blockers. Hippocampal slices were cultured and treated with micromolar concentrations of dopamine, with or without dopamine receptor blockers. Last, levels of dysbindin, a regulator of the membrane availability of dopamine receptors, were assessed in the experimental model and in brain samples from ventilated patients. MEASUREMENTS AND MAIN RESULTS: Mechanical ventilation triggers hippocampal apoptosis as a result of type 2 dopamine receptor activation in response to vagal signaling. Activation of these receptors blocks the Akt/GSK3ß prosurvival pathway and activates the apoptotic cascade, as demonstrated in vivo and in vitro. Vagotomy, systemic haloperidol, or intracerebroventricular raclopride (a type 2 dopamine receptor blocker) ameliorated this effect. Moreover, ventilation induced a concomitant change in the expression of dysbindin-1C. These results were confirmed in brain samples from ventilated patients. CONCLUSIONS: These results prove the existence of a pathogenic mechanism of lung stretch-induced hippocampal apoptosis that could explain the neurological changes in ventilated patients and may help to identify novel therapeutic approaches.


Assuntos
Apoptose , Dopamina/metabolismo , Hipocampo/patologia , Respiração Artificial/efeitos adversos , Nervo Vago/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Disbindina , Proteínas Associadas à Distrofina , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Nervo Vago/metabolismo
14.
Respir Res ; 14: 52, 2013 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-23663489

RESUMO

BACKGROUND: Mechanical ventilation can promote lung injury by triggering a pro-inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury. METHODS: Adult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH2O, PEEP 2 cmH2O) or high (20 cmH2O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFκB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed. RESULTS: There were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFκB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin. CONCLUSIONS: Clarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Claritromicina/uso terapêutico , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Animais , Mediadores da Inflamação/sangue , Levofloxacino/uso terapêutico , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
15.
Am J Physiol Lung Cell Mol Physiol ; 304(12): L844-52, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23585228

RESUMO

Excessive lung stretch triggers lung inflammation by activation of the NF-κB pathway. This route can be modulated by autophagy, an intracellular proteolytic system. Our objective was to study the impact of the absence of autophagy in a model of ventilator-induced lung injury. Mice lacking Autophagin-1/ATG4B (Atg4b-/-), a critical protease in the autophagic pathway, and their wild-type counterparts were studied in baseline conditions and after mechanical ventilation. Lung injury, markers of autophagy, and activation of the inflammatory response were evaluated after ventilation. Mechanical ventilation increased autophagy and induced lung injury in wild-type mice. Atg4b-/- animals showed a decreased lung injury after ventilation, with less neutrophilic infiltration than their wild-type counterparts. As expected, autophagy was absent in mutant animals, resulting in the accumulation of p62 and ubiquitinated proteins. Activation of the canonical NF-κB pathway was present in ventilated wild-type, but not Atg4b-deficient, animals. Moreover, these mutant mice showed an accumulation of ubiquitinated IκB. High-pressure ventilation partially restored the autophagic response in Atg4b-/- mice and abolished the differences between genotypes. In conclusion, impairment of autophagy results in an ameliorated inflammatory response to mechanical ventilation and decreases lung injury. The accumulation of ubiquitinated IκB may be responsible for this effect.


Assuntos
Cisteína Endopeptidases/genética , Pulmão/metabolismo , NF-kappa B/genética , Transdução de Sinais/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia , Cisteína Endopeptidases/deficiência , Citocinas/biossíntese , Regulação da Expressão Gênica , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Inflamação/genética , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Infiltração de Neutrófilos/genética , Respiração Artificial/efeitos adversos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitinação , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
16.
PLoS One ; 7(6): e39940, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22768176

RESUMO

Matrix metalloproteinase-8, released mainly from neutrophils, is a critical regulator of the inflammatory response by its ability to cleave multiple mediators. Herein, we report the results of a model of endotoxemia after intraperitoneal LPS injection in mice lacking MMP-8 and their wildtype counterparts. Control, saline-treated animals showed no differences between genotypes. However, there was an increased lung inflammatory response, with a prominent neutrophilic infiltration in mutant animals after LPS treatment. Using a proteomic approach, we identify alarmins S100A8 and S100A9 as two of the main differences between genotypes. Mice lacking MMP-8 showed a significant increase in these two molecules in lung homogenates, but not in spleen and serum. Mice lacking MMP-8 also showed an increase in MIP-1α levels and a marked activation of the non-canonical NF-κB pathway, with no differences in CXC-chemokines such as MIP-2 or LIX. These results show that MMP-8 can modulate the levels of S100A8 and S100A9 and its absence promotes the lung inflammatory response during endotoxemia.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Endotoxemia/enzimologia , Metaloproteinase 8 da Matriz/deficiência , Pneumonia/enzimologia , Receptores Imunológicos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Endotoxemia/complicações , Endotoxemia/imunologia , Endotoxemia/patologia , Genótipo , Ligantes , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Pneumonia/complicações , Pneumonia/imunologia , Pneumonia/patologia , Proteômica , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais/efeitos dos fármacos
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