Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury

Introduction: Acute respiratory distress syndrome (ARDS) is an acute form of diffuse lung injury characterized by (i) an intense inflammatory response, (ii) increased pulmonary vascular permeability, and (iii) the loss of respiratory pulmonary tissue. In this article we explore the therapeutic potential of hexarelin, a synthetic hexapeptide growth hormone secretagogue (GHS), in an experimental model of ARDS. Hexarelin has anti-inflammatory properties and demonstrates cardiovascular-protective activities including the inhibition of cardiomyocyte apoptosis and cardiac fibrosis, both of which may involve the angiotensin-converting enzyme (ACE) system. Methods: In our experimental model, ARDS was induced by the instillation of 100 mM HCl into the right bronchus; these mice were treated with hexarelin (320 μg/kg, ip) before (Pre) or after (Post) HCl challenge, or with vehicle. Respiratory system compliance, blood gas analysis, and differential cell counts in a selective bronchoalveolar lavage (BAL) were determined 6 or 24 hours after HCl instillation. In an extended study, mice were observed for a subsequent 14 days in order to assess lung fibrosis. Results: Hexarelin induced a significant improvement in lung compliance and a reduction of the number of total immune cells in BAL 24 hours after HCl instillation, accompanied with a lower recruitment of neutrophils compared with the vehicle group. At day 14, hexarelin-treated mice presented with less pulmonary collagen deposition compared with vehicle-treated controls. Conclusions: Our data suggest that hexarelin can inhibit the early phase of the inflammatory response in a murine model of HCl-induced ARDS, thereby blunting lung remodeling processes and fibrotic development.

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Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00012.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. L336-L345 ◽

Cited By ~ 22

Author(s):

Amir M. Abushamaa ◽

Thomas A. Sporn ◽

Rodney J. Folz

Keyword(s):

Breast Cancer ◽

Oxidative Stress ◽

Lung Injury ◽

Inflammatory Response ◽

Chemotherapeutic Agents ◽

Total Cell ◽

Lung Toxicity ◽

High Dose ◽

Cell Counts ◽

Cellular Inflammatory Response

Delayed pulmonary toxicity syndrome after high-dose chemotherapy (HDC) and autologous hematopoietic support occurs in up to 64% of women with advanced-stage breast cancer. Using a similar, but nonmyeloablative, HDC treatment regimen in mice, we found both immediate and persistent lung injury, coincident with marked decreases in lung tissue glutathione reductase activity and accompanied by increases in lung oxidized glutathione, bronchoalveolar lavage (BAL) lipid peroxidation, and BAL total cell counts. Most interestingly, at 6 wk, BAL total cell counts had increased fourfold, with lymphocyte cell counts increasing >11-fold. A single supplemental dose of glutathione prevented early lung injury at 48 h but showed no lung-protective effects at 6 wk, whereas single doses of other thiol-sparing agents (Ethyol and glutathione monoethyl ester) showed no benefit. These data suggest that this HDC regimen results in acute and persistent lung toxicity, induced in part by oxidative stress, that culminates with an acute lung cellular inflammatory response. Continuous glutathione supplementation and/or attenuation of the delayed pulmonary inflammatory response may prove beneficial in preventing lung toxicity after the use of these chemotherapeutic agents.

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Effects of Various Modes of Mechanical Ventilation in Normal Rats

Anesthesiology ◽

10.1097/aln.0000000000000075 ◽

2014 ◽

Vol 120 (4) ◽

pp. 943-950 ◽

Cited By ~ 11

Author(s):

Matteo Pecchiari ◽

Ario Monaco ◽

Antonia Koutsoukou ◽

Patrizia Della Valle ◽

Guendalina Gentile ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Inflammatory Response ◽

Negative Pressure ◽

Positive Pressure Ventilation ◽

Lung Mechanics ◽

Whole Body ◽

Positive Pressure ◽

Negative Pressure Ventilation ◽

Cytokine Levels

Abstract Background: Recent studies in healthy mice and rats have reported that positive pressure ventilation delivered with physiological tidal volumes at normal end-expiratory volume worsens lung mechanics and induces cytokine release, thus suggesting that detrimental effects are due to positive pressure ventilation per se. The aim of this study in healthy animals is to assess whether these adverse outcomes depend on the mode of mechanical ventilation. Methods: Rats were subjected to 4 h of spontaneous, positive pressure, and whole-body or thorax-only negative pressure ventilation (N = 8 per group). In all instances the ventilatory pattern was that of spontaneous breathing. Lung mechanics, cytokines concentration in serum and broncho–alveolar lavage fluid, lung wet-to-dry ratio, and histology were assessed. Values from eight animals euthanized shortly after anesthesia served as control. Results: No evidence of mechanical ventilation–dependent lung injury was found in terms of lung mechanics, histology, or wet-to-dry ratio. Relative to control, cytokine levels and recruitment of polymorphonuclear leucocytes increased slightly, and to the same extent with spontaneous, positive pressure, and whole-body negative pressure ventilation. Thorax-only negative pressure ventilation caused marked chest and lung distortion, reversible increase of lung elastance, and higher polymorphonuclear leucocyte count and cytokine levels. Conclusion: Both positive and negative pressure ventilation performed with tidal volumes and timing of spontaneous, quiet breathing neither elicit an inflammatory response nor cause morpho-functional alterations in normal animals, thus supporting the notion of the presence of a critical volume threshold above which acute lung injury ensues. Distortion of lung parenchyma can induce an inflammatory response, even in the absence of volotrauma.

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Attenuation of pulmonary injury by an inhaled MMP inhibitor in the endotoxin lung injury model

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00420.2019 ◽

2020 ◽

Vol 319 (6) ◽

pp. L1036-L1047

Author(s):

Adam Gerber ◽

Monica Goldklang ◽

Kyle Stearns ◽

Xinran Ma ◽

Rui Xiao ◽

...

Keyword(s):

Lung Injury ◽

Pulmonary Edema ◽

Pulmonary Inflammation ◽

Neutrophil Migration ◽

Neutrophil Infiltration ◽

Vascular Integrity ◽

Pulmonary Vascular Permeability ◽

Mmp Inhibitor ◽

Cell Counts ◽

Lung Injury Model

Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema and poor gas exchange resulting from severe inflammatory lung injury. Neutrophilic infiltration and increased pulmonary vascular permeability are hallmarks of early ARDS and precipitate a self-perpetuating cascade of inflammatory signaling. The biochemical processes initiating these events remain unclear. Typically associated with extracellular matrix degradation, recent data suggest matrix metalloproteinases (MMPs) are regulators of pulmonary inflammation. To demonstrate that inhalation of a broad MMP inhibitor attenuates LPS induced pulmonary inflammation. Nebulized CGS27023AM (CGS) was administered to LPS-injured mice. Pulmonary CGS levels were examined by mass spectroscopy. Inflammatory scoring of hematoxylin-eosin sections, examination of vascular integrity via lung wet/dry and bronchoalveolar lvage/serum FITC-albumin ratios were performed. Cleaved caspase-3 levels were also assessed. Differential cell counts and pulse-chase labeling were utilized to determine the effects of CGS on neutrophil migration. The effects of CGS on human neutrophil migration and viability were examined using Boyden chambers and MTT assays. Nebulization successfully delivered CGS to the lungs. Treatment decreased pulmonary inflammatory scores, edema, and apoptosis in LPS treated animals. Neutrophil chemotaxis was reduced by CGS treatment, with inhalation causing significant reductions in both the total number and newly produced bromodeoxyuridine-positive cells infiltrating the lung. Mechanistic studies on cells isolated from humans demonstrate that CGS-treated neutrophils exhibit decreased chemotaxis. The protective effect observed following treatment with a nonspecific MMP inhibitor indicates that one or more MMPs mediate the development of pulmonary edema and neutrophil infiltration in response to LPS injury. In accordance with this, inhaled MMP inhibitors warrant further study as a potential new therapeutic avenue for treatment of acute lung injury.

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Methylprednisolone improves lung mechanics and reduces the inflammatory response in pulmonary but not in extrapulmonary mild acute lung injury in mice*

Critical Care Medicine ◽

10.1097/ccm.0b013e3181847b43 ◽

2008 ◽

Vol 36 (9) ◽

pp. 2621-2628 ◽

Cited By ~ 36

Author(s):

José Henrique P. Leite-Junior ◽

Cristiane S.N.B. Garcia ◽

Alba B. Souza-Fernandes ◽

Pedro L. Silva ◽

Debora S. Ornellas ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Lung Mechanics

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Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00096.2013 ◽

2014 ◽

Vol 306 (3) ◽

pp. L233-L245 ◽

Cited By ~ 18

Author(s):

Hironobu Tsubouchi ◽

Shigehisa Yanagi ◽

Ayako Miura ◽

Seiichi Iizuka ◽

Sachiko Mogami ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Proinflammatory Cytokines ◽

Lung Fibrosis ◽

Gastrointestinal Symptoms ◽

Alveolar Epithelial Cells ◽

Therapeutic Effects ◽

Growth Hormone Secretagogue ◽

Pulmonary Vascular Permeability ◽

Deficient Mice

Acute lung injury (ALI) is a critical syndrome consisting of acute respiratory failure associated with extensive pulmonary infiltrates. The pathological characterization of ALI includes injuries of alveolar epithelial cells (AECs), alveolar neutrophilic infiltration, and increases in proinflammatory cytokines, which cause destruction of the alveolar capillary barrier and subsequent devastating lung fibrosis. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment of patients with gastrointestinal symptoms and is known to stimulate ghrelin secretion. The therapeutic effects of RKT on organ inflammation and fibrosis remain unknown. We investigated the pharmacological potential of RKT in the treatment of ALI by using a bleomycin-induced ALI model in mice. RKT or distilled water (DW) was given to mice daily starting 12 h after bleomycin administration. The RKT-treated mice showed a definitively higher survival rate than the DW-treated mice after injury. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of proinflammatory cytokines, activation of the NF-κB pathway, apoptosis of AECs, and subsequent lung fibrosis were notable in the RKT-treated mice. RKT administration increased the plasma ghrelin levels in wild-type mice, and it also mitigated the ALI response in both ghrelin-deficient mice and growth hormone secretagogue receptor-deficient mice after lung injury. Our results indicate that RKT administration exerts protective effects against ALI by protecting the AECs and regulating lung inflammation independently of the ghrelin system, and they highlight RKT as a promising therapeutic agent for the management of this intractable disease.

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Does Early Posttreatment with Lidocaine Attenuate Endotoxin-induced Acute Lung Injury in Rabbits?

Anesthesiology ◽

10.1097/00000542-199507000-00020 ◽

1995 ◽

Vol 83 (1) ◽

pp. 169-177. ◽

Cited By ~ 22

Author(s):

Kahoru Nishina ◽

Katsuya Mikawa ◽

Nobuhiro Maekawa ◽

Yumiko Takao ◽

Hidefumi Obara

Keyword(s):

Acute Lung Injury ◽

Treatment Group ◽

Lung Injury ◽

Weight Ratio ◽

Lung Damage ◽

Lung Mechanics ◽

Lung Edema ◽

Platelet Counts ◽

Peripheral Leukocyte ◽

Cell Counts

Background It is well known that endotoxin causes acute lung injury, resulting in adult respiratory distress syndrome. Lidocaine pretreatment has recently been shown to attenuate endotoxin-induced lung injury in rabbits. The aim of the current study was to determine whether early postinjury treatment with intravenous lidocaine could attenuate acute lung injury induced by endotoxin in rabbits. Methods Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline (group S-S), infusion of saline with lidocaine treatment (group S-L), infusion of Escherichia coli endotoxin (100 micrograms.kg-1 over a 60-min period) without lidocaine treatment (group E-S), or infusion of endotoxin with lidocaine treatment (group E-L). Ten minutes after the end of infusion of endotoxin (groups E-L and E-S) or saline (groups S-S and S-L), the animals received a bolus injection followed by continuous infusion of lidocaine (2 mg.kg-1 + 2 mg.kg-1.h-1 in groups S-L and E-L) or saline (groups S-S and E-S). The rabbits' lungs were ventilated with 40% O2. Hemodynamics, peripheral leukocyte and platelet counts, and arterial O2 tension (PaO2) were recorded during the ventilation period (6 h). After the observation, lung mechanics; the cell fraction of bronchoalveolar lavage fluid (BALF); and concentrations of activated complement components C3a and C5a, cytokines, and arachidonic acid metabolites in BALF were measured and analyzed. The ratio of lung wet weight to dry weight (W/D weight ratio) and albumin concentrations in BALF were analyzed as indexes of pulmonary edema. The Cypridina luciferin analogue-dependent chemiluminescence (representing O2 production) by neutrophils isolated from the pulmonary artery and light-microscopic findings of the lung were compared among the four groups. Results Endotoxin caused decreases in peripheral leukocyte and platelet counts, lung compliance, and PaO2. It caused increases in lung W/D weight ratio; polymorphonuclear cell counts in BALF; and albumin, C3a, C5a, tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and thromboxane B2 concentrations in BALF. Lidocaine attenuated the changes in W/D weight ratio and morphologic lung damage. The change in compliance, decrease in PaO2, and albumin concentrations in BALF were slightly but significantly less in rabbits receiving lidocaine after injury. The Cypridina luciferin analogue-dependent chemiluminescence by neutrophils was greater in rabbits receiving endotoxin without lidocaine than in those receiving endotoxin with lidocaine. Conclusions These results indicate that early treatment with lidocaine attenuates endotoxin-induced lung edema in rabbits without affecting chemical mediators in BALF. However, the improvement is slight and likely to be of little clinical significance.

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Role of Ethyl Pyruvate in Systemic Inflammatory Response and Lung Injury in an Experimental Model of Ruptured Abdominal Aortic Aneurysm

BioMed Research International ◽

10.1155/2014/857109 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Zerrin Pulathan ◽

Gökalp Altun ◽

Doğuş Hemşinli ◽

Ahmet Menteşe ◽

Esin Yuluğ ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Response ◽

Experimental Model ◽

Ethyl Pyruvate ◽

Ischemia Reperfusion ◽

Systemic Inflammatory Response ◽

Male Rats ◽

Sprague Dawley ◽

Necrosis Factor Alpha ◽

Abdominal Aortic

Objectıve. The purpose of this study is to evaluate the effect of ethyl pyruvate (EP) on systemic inflammatory response and lung injury in an experimental rat model of ruptured abdominal aortic anurysm (RAAA).Methods. Anaesthetized 30 Sprague-Dawley male rats were randomized to sham (Shn:6) (Sh + EPn:6) or shock and clamp (S/C) groups (S/Cn:9) (S/C + EPn:9). In the S/C and S/C + EP groups, hemorrhagic shock, lower torso ischemia, and reperfusion were created, S/C group was given 1 mL saline and S/C + EP group was given 40 mg/kg EP. At the end of reperfusion process some biochemical and histological parameters were studied in serum and lung tissues.Results. An increase was observed in all parameters except interleukin-6 (IL-6) in the S/C group in comparison to the sham groups. In the S/C + EP group, serum myeloperoxydase (MPO), malondialdehyde (MDA), and tumor necrosis factor alpha (TNF-α) as well as lung MPO and MDA values decreased significantly (P<0.016). In the lung tissues, histological injury scores and lung tissue wet/dry ratio were significantly decreased in the S/C + EP group as compared to the S/C group (P<0.016).Conclusions. Ethyl pyruvate may reduce systemic inflammatory response and lung injury which resulted from shock and ischemia/reperfusion in an experimental model of RAAA.

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Mechanical Ventilation Affects Lung Function and Cytokine Production in an Experimental Model of Endotoxemia

Anesthesiology ◽

10.1097/00000542-200502000-00015 ◽

2005 ◽

Vol 102 (2) ◽

pp. 331-339 ◽

Cited By ~ 55

Author(s):

Fabienne Brégeon ◽

Stéphane Delpierre ◽

Bruno Chetaille ◽

Osamu Kajikawa ◽

Thomas R Martin ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Blood Gases ◽

Lung Mechanics ◽

Positive Pressure ◽

Positive End Expiratory Pressure ◽

Cell Counts ◽

Volume Controlled Ventilation ◽

Spontaneously Breathing

Background Mechanical ventilation using tidal volumes around 10 ml/kg and zero positive end-expiratory pressure is still commonly used in anesthesia. This strategy has been shown to aggravate lung injury and inflammation in preinjured lungs but not in healthy lungs. In this study, the authors investigated whether this strategy would result in lung injury during transient endotoxemia in the lungs of healthy animals. Methods Volume-controlled ventilation with a tidal volume of 10 ml/kg and zero positive end-expiratory pressure was applied in two groups of anesthetized-paralyzed rabbits receiving either intravenous injection of 5 mug/kg Escherichia coli lipopolysaccharide (n = 10) or saline (n = 10) 2 h after the start of mechanical ventilation. The third group consisted of 10 spontaneously breathing anesthetized animals receiving lipopolysaccharide. Anesthesia was then continued for 4 h in the three groups while the ventilatory modes were maintained unchanged. Lung injury was studied using blood gases, respiratory physiologic variables, analysis of the bronchoalveolar lavage cell counts, and cytokine concentrations and lung pathologic examination. Results Significant histologic lung alterations, hypoxemia, and altered lung mechanics were observed in rabbits treated with mechanical ventilation and intravenous lipopolysaccharide but not in the mechanically ventilated animals injected with saline or in spontaneously breathing animals treated with lipopolysaccharide. Endotoxemic ventilated animals also had significantly more lung inflammation as assessed by the alveolar concentration of neutrophils, and the concentrations of the chemokines interleukin 8 and growth-related oncogen alpha. Conclusions These results showed that positive-pressure mechanical ventilation using a tidal volume of 10 ml/kg and zero positive end-expiratory pressure was harmful in the setting of endotoxemia, suggesting that the use of this ventilator strategy in the operating room may predispose to lung injury when endotoxemia occurs.

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Effect of low-level laser therapy on the inflammatory response in an experimental model of ventilator-induced lung injury

Photochemical & Photobiological Sciences ◽

10.1039/d0pp00053a ◽

2020 ◽

Vol 19 (10) ◽

pp. 1356-1363

Author(s):

Thaís Fernanda Fazza ◽

Bruno Valle Pinheiro ◽

Lídia Maria Carneiro da Fonseca ◽

Luiz Philippe da Silva Sergio ◽

Mateus Pinto Botelho ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Response ◽

Laser Therapy ◽

Experimental Model ◽

Low Level Laser Therapy ◽

Lung Injury Score ◽

Low Level ◽

Low Level Laser ◽

Ventilator Induced Lung Injury ◽

Level Laser

The effect of low-level laser therapy (LLLT) on an experimental model of ventilator-induced lung injury (VILI) was evaluated in this study. LLLT reduced the inflammatory response by reduction of the lung injury score.

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Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages

Metabolites ◽

10.3390/metabo11090592 ◽

2021 ◽

Vol 11 (9) ◽

pp. 592

Author(s):

Alessandro Del Re ◽

Chiara Corpetti ◽

Marcella Pesce ◽

Luisa Seguella ◽

Luca Steardo ◽

...

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Therapeutic Potential ◽

Primary Cultures ◽

Signalling Pathway ◽

Vehicle Group ◽

Immunomodulatory Activity ◽

Tnf Α ◽

Anti Inflammatory ◽

Significant Concentration

Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1β) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1β, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in ACE-2 following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.

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