Role of Focal Adhesion Kinase in Lung Remodeling of Endotoxemic Rats

Petroni, Ricardo; Teodoro, Walcy Rosolia; Guido, Maria Carolina; Barbeiro, Hermes Vieira; Abatepaulo, Fatima; Theobaldo, Mariana Cardillo; Biselli, Paolo Cesare; Soriano, Francisco Garcia

doi:10.1097/shk.0b013e31824c7665

Cited by 12 publications

(13 citation statements)

References 26 publications

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“…LPS-induced ALI is known to be associated with respiratory mechanical changes represented by compliance reduction and elevated pulmonary resistance (21). As expected, endotoxemic animals presented with decreased lung function, similar to that observed in ALI patients.…”

Section: Discussionsupporting

confidence: 72%

“…Some studies have shown that in ALI, type III collagen (characterized by elastic properties) may be replaced by type I collagen (more resistant), which explains the worst degree of pulmonary function (21,29). We showed that precocious hypertonic saline fluid resuscitation decreased type I collagen and increased type III collagen deposition in pulmonary tissue.…”

Section: Discussionmentioning

confidence: 87%

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Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury

Petroni

Biselli²,

Lima³

et al. 2015

Shock

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Acute lung injury (ALI) is a common complication associated with septic shock that directly influences the prognosis of sepsis patients. Currently, one of the main supportive treatment modalities for septic shock is fluid resuscitation. The use of hypertonic saline (HS: 7.5% NaCl) for fluid resuscitation has been described as a promising therapy in experimental models of sepsis-induced ALI, but it has failed to produce similar results in clinical practice. Thus, we compared experimental timing versus clinical timing effectiveness (i.e., early vs. late fluid resuscitation) after the inflammatory scenario was established in a rat model of bacterial lipopolysaccharide-induced ALI. We found that late fluid resuscitation with hypertonic saline (NaCl 7.5%) did not reduce the mortality rates of animals compared with the mortality late associated with early treatment. Late fluid resuscitation with both hypertonic and normal saline increased pulmonary inflammation, decreased pulmonary function, and induced pulmonary injury by elevating metalloproteinase-2 and metalloproteinase-9 activity and collagen deposition in the animals, unlike early treatment. The animals with lipopolysaccharide-induced ALI that received late resuscitation with any kind of fluids demonstrated aggravated pulmonary injury and respiratory function. Moreover, we showed that the therapeutic window for a beneficial effect of fluid resuscitation with hypertonic saline is very narrow.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 87%

Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury

Petroni

Biselli²,

Lima³

et al. 2015

Shock

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“…The ECM remodeling process, in response to an acute or chronic inflammatory injury, involves synthesis and degradation balance (27). In our previous study, we observed increased cardiac deposition of collagen in patients who died from septic shock (2), and we observed a similar pattern in an experimental endotoxemia model (16,18). The FAK reportedly participates in the Toll-like receptor signaling pathway and is activated by cytokines and oxidative stress (28).…”

Section: Myocardial Dysfunction In Endotoxemiasupporting

confidence: 71%

Endotoxemic Myocardial Dysfunction

Soriano¹,

Guido

Barbeiro

et al. 2014

Shock

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Sepsis impairs the autoregulation of myocardial microcirculatory blood flow, but whether this impairment is correlated with myocardial remodeling is unknown. This study investigated the role of coronary driving pressure (CDP) as a determinant of microcirculatory blood flow and myocardial fibrosis in endotoxemia and sepsis. The study is composed of two parts: a prospective experimental study and an observational clinical study. The experimental study was performed on male Wistar rats weighing 300 to 320 g. Endotoxemia was induced in rats by lipopolysaccharide (LPS) injection (10 mg·kg intraperitoneally). Hemodynamic evaluation was performed 1.5 to 24 h after LPS injection by measuring the mean arterial pressure, CDP, left ventricular end-diastolic pressure, dP/dtmax, and dP/dtmin. Microspheres were also infused into the left ventricle to measure myocardial blood flow, and myocardial tissue was histologically assessed to analyze collagen deposition. The CDP, mean arterial pressure, and myocardial blood flow were reduced by 55%, 30%, and 70%, respectively, in rats 1.5 h after LPS injection compared with phosphate buffer saline injection (P < 0.05). The CDP was significantly correlated with subendocardial blood flow (r = 0.73) and fibrosis (r = 0.8). Left ventricular function was significantly impaired in the LPS-treated rats, as demonstrated by dP/dtmax (6,155 ± 455 vs. 3,746 ± 406 mmHg·s, baseline vs. LPS; P < 0.05) and dP/dtmin (-5,858 ± 236 vs. -3,516 ± 436 mmHg·s, baseline vs. LPS; P < 0.05). The clinical study was performed on 28 patients with septic shock analyzed for CDP. The CDP data and histological slices were collected from septic patients. In addition, the clinical data demonstrated fibrosis and 45% CDP reduction in nonsurvivors compared with survivors. In conclusion, the left ventricular subendocardial blood flow was positively correlated with CDP, and higher CDP was negatively correlated with myocardial collagen deposition. Thus, early reductions in myocardial blood flow and CDP facilitate late myocardial fibrosis in rats and likely in humans.

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“…Our findings indicate that FAK mediates the ET-1-elevated expression level of HMGB1 in HBEpCs, suggesting that the functional role of FAK in ALI is at least partially fulfilled through the ET-1/HMGB1 axis. FAK reportedly can promote lung collagen deposition [26] , which favors development of pulmonary fibrosis in patients with ARDS [27] . Abnormal HMGB1 activation is involved in the pathogenesis of pulmonary fibrosis [28] .…”

Section: Discussionmentioning

confidence: 99%

“…How ET-1/ETA signaling enhances the HMGB1 mRNA stability via FAK in HBEpCs will be explored in our future studies. In addition, FAK has been shown to play a critical role in ALI and in the septic lung remodeling process [26] . Our findings indicate that FAK mediates the ET-1-elevated expression level of HMGB1 in HBEpCs, suggesting that the functional role of FAK in ALI is at least partially fulfilled through the ET-1/HMGB1 axis.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 Upregulates the Expression of High Mobility Group Box 1 in Human Bronchial Epithelial Cells

Guan

Long

et al. 2015

Pharmacology

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Both endothelin-1 (ET-1) and high mobility group box 1 (HMGB1) reportedly are closely involved in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In this study, we explored the regulatory effects of ET-1 on the expression of HMGB1 in human bronchial epithelial cells (HBEpCs). Primary HBEpCs were treated with ET-1 with or without transcription inhibitor actinomycin D, ETA receptor blocker BQ123, ETB receptor blocker BQ788, focal adhesion kinase (FAK) inhibitor or shRNA, or different kinase inhibitors. ET-1 increased the HMGB1 mRNA level in a statistically significant dose- and time-dependent manner within 8 hours of treatment, which was reflected in the dose-dependent induction of the HMGB1 protein level and the FAK activity. BQ123 and FAK inhibitor or shRNA, but not BQ788, completely abolished the promoting effect of ET-1 on the expression of HMGB1. Luciferase reporter assays revealed that neither ET-1 nor ETA nor FAK inhibition had any significant effect on the HMGB1 gene promoter activity. In the presence of the transcription inhibitor actinomycin D, the HMGB1 mRNA level markedly decreased over time, and ET-1 dose-dependently rescued the HMGB1 mRNA level. This effect of ET-1 was completely abolished by BQ123 and FAK inhibitor or shRNA, but not by BQ788. In conclusion, this study provides the first evidence that ET-1 upregulates the expression of HMGB1 in HBEpCs by increasing the stability of HMGB1 mRNA via the ETA receptor by a FAK-dependent mechanism. It adds new insights into the molecular mechanisms underlying ALI/ARDS.

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Role of Focal Adhesion Kinase in Lung Remodeling of Endotoxemic Rats

Cited by 12 publications

References 26 publications

Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury

Impact of Time on Fluid Resuscitation with Hypertonic Saline (NaCl 7.5%) in Rats with LPS-Induced Acute Lung Injury

Endotoxemic Myocardial Dysfunction

Endothelin-1 Upregulates the Expression of High Mobility Group Box 1 in Human Bronchial Epithelial Cells

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