Alpha 1-antitrypsin ameliorates ventilator-induced lung injury in rats by inhibiting inflammatory responses and apoptosis

Mechanical ventilation is extensively used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). The present study investigated the protective effect of alpha 1-antitrypsin (AAT) on VILI. Adult male rats were subjected to sham, ventilation + saline, or ventilation + AAT treatment and lung injuries were evaluated. Peripheral blood and bronchoalveolar lavage fluid (BALF) were obtained to assess systemic and local inflammatory responses, respectively. Mechanical ventilation resulted in lung injury, as evidenced by histological abnormalities as well as elevations in PaO2/FiO2 ratio, the wet-to-dry weight ratio, and the BALF level of proteins. The intravenous administration of AAT significantly improved these parameters of lung function, suggesting a protective role of AAT in VILI. Mechanistically, ventilator-induced inflammation was effectively reduced by AAT, as evidenced by decreases in BALF neutrophil counts, BALF cytokines, and serum adhesion factors. In contrast, anti-inflammatory interleukin-10 in BALF was increased in response to AAT. AAT treatment also inhibited the expression of nuclear factor-κB, Bax, and cleaved caspase-3 while promoting Bcl-2 expression in ventilator-injured lung tissues. AAT treatment can ameliorate VILI by inhibiting inflammatory mediator production and apoptosis. Impact statement Mechanical ventilation has been commonly used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). Few effective treatment options are currently available to reduce VILI. Alpha 1-antitrypsin (AAT) is an inhibitor of serine protease with anti-inflammatory and antiapoptotic properties, suggesting a possible role in attenuating lung injury. The present study demonstrates that AAT inhibits the development of VILI by modulating inflammation- and apoptosis-related protein expression. Therefore, AAT may be a novel therapeutic agent for acute respiratory distress syndrome patients undergoing mechanical ventilation.

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Inhibition of Poly(Adenosine Diphosphate–Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

Anesthesiology ◽

10.1097/01.anes.0000299434.86640.15 ◽

2008 ◽

Vol 108 (2) ◽

pp. 261-268 ◽

Cited By ~ 37

Author(s):

Rosanna Vaschetto ◽

Jan W. Kuiper ◽

Shyh Ren Chiang ◽

Jack J. Haitsma ◽

Jonathan W. Juco ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Interleukin 6 ◽

Inflammatory Responses ◽

Adenosine Diphosphate ◽

High Tidal Volume ◽

Positive End Expiratory Pressure ◽

Ventilator Induced Lung Injury ◽

Pharmacologic Inhibition

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

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Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00349.2011 ◽

2012 ◽

Vol 302 (4) ◽

pp. L370-L379 ◽

Cited By ~ 24

Author(s):

Dejie Liu ◽

Zhibo Yan ◽

Richard D. Minshall ◽

David E. Schwartz ◽

Yuguo Chen ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Neutrophil Recruitment ◽

Calpain Activation ◽

Ventilator Induced Lung Injury ◽

Volume Ventilation ◽

Calpain 2

Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.

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Neutrophil-Derived IL-17 Promotes Ventilator-Induced Lung Injury via p38 MAPK/MCP-1 Pathway Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.768813 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoting Liao ◽

Weikang Zhang ◽

Huijun Dai ◽

Ren Jing ◽

Mengling Ye ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Critical Role ◽

Mitogen Activated Protein Kinase ◽

Interleukin 17 ◽

Ventilator Induced Lung Injury ◽

Mitogen Activated Protein

Ventilator-induced lung injury (VILI) is one of the most common complications of mechanical ventilation and can severely affect health. VILI appears to involve excessive inflammatory responses, but its pathogenesis has not yet been clarified. Since interleukin-17 (IL-17) plays a critical role in the immune system and the development of infectious and inflammatory diseases, we investigated here whether it plays a role in VILI. In a mouse model of VILI, mechanical ventilation with high tidal volume promoted the accumulation of lung neutrophils, leading to increased IL-17 levels in the lung, which in turn upregulated macrophage chemoattractant protein-1 via p38 mitogen-activated protein kinase. Depletion of neutrophils decreases the production IL-17 in mice and inhibition of IL-17 significantly reduced HTV-induced lung injury and inflammatory response. These results were confirmed in vitro using RAW264.7 macrophage cultures. Our results suggest that IL-17 plays a pro-inflammatory role in VILI and could serve as a new target for its treatment.

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Protective Effect of Oxytocin on Ventilator-Induced Lung Injury Through NLRP3-Mediated Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2021.722907 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaomei Yang ◽

Xiaona An ◽

Cheng Wang ◽

Feng Gao ◽

Yicheng Lin ◽

...

Keyword(s):

Lung Injury ◽

Bronchoalveolar Lavage ◽

Protective Effect ◽

Bronchoalveolar Lavage Fluid ◽

Life Support ◽

Inflammatory Responses ◽

Weight Ratio ◽

Lavage Fluid ◽

Caspase 1 ◽

Ventilator Induced Lung Injury

Mechanical ventilation is an indispensable life-support treatment for acute respiratory failure in critically ill patients, which is generally believed to involve uncontrolled inflammatory responses. Oxytocin (OT) has been reported to be effective in animal models of acute lung injury. However, it is not clear whether Oxytocin has a protective effect on ventilator-induced lung injury (VILI). Therefore, in this study, we aimed to determine whether OT can attenuate VILI and explore the possible mechanism of this protection. To this end, a mouse VILI model was employed. Mice were pretreated with OT 30 min before the intraperitoneal injection of saline or nigericin and ventilation for 4 h, after which they were euthanized. Pathological changes, lung wet/dry (W/D) weight ratio, myeloperoxidase (MPO) activity, the levels of inflammatory cytokines [i.e., interleukin (IL)-1β, IL-6, and IL-18] in lung tissues and bronchoalveolar lavage fluid (BALF), and expression of NLRP3, Toll-like receptor 4 (TLR4), caspase-1, nuclear factor (NF)-κB, and GSDMD in lung tissues were measured. OT treatment could reduce pathological injury, the W/D ratio, and MPO activity in VILI mice. Our data also indicated that OT administration alleviated the expression of TLR4/My-D88 and the activation of NF-κB, NLRP3, and caspase-1 in lung tissues from the VILI mice model. Furthermore, OT also decreased the levels of IL-1β, IL-6, and IL-18 in the bronchoalveolar lavage fluid. Moreover, the OT administration may alleviate the activation of GSDMD partially through its effects on the NLRP3-mediated pathway. Collectively, OT exerted a beneficial effect on VILI by downregulating TLR4-and NLRP3-mediated inflammatory pathways.

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Marathoners’ breathing pattern protects against lung injury by mechanical ventilation: a pilot study

10.21203/rs.2.21360/v1 ◽

2020 ◽

Author(s):

Yoshiaki Oshima ◽

Naoto Okazaki ◽

Akihiro Otsuki ◽

Shunsaku Takahashi ◽

Tomomi Harada ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Time Allocation ◽

Breathing Pattern ◽

Weight Ratio ◽

Dry Weight ◽

Clinical Settings ◽

Protective Effects ◽

Ventilator Induced Lung Injury ◽

Novel Method

Abstract Background: Marathoners use the 2:2 breathing pattern. We hypothesized that this ventilation method may protect against ventilator-induced lung injury.Methods: We studied the 2:2 breathing pattern as a mechanical ventilation mode, by assessing the gas exchange in intact rabbits and the pulmonary protective effects in isolated rabbit lungs. The typical setting of this breathing method was 30 cycles/min of respiratory frequency. The time allocation for one cycle was as follows: 1st inspiratory period, 2nd inspiratory period, 1st expiratory period, and 2nd expiratory period (all 0.3 s long) with intermittent resting periods (all 0.2 s).Results: The 2:2 breathing pattern caused no problems regarding the efficiency of oxygen uptake and carbon dioxide elimination. The wet-to-dry weight ratio of the lung was lower for the proposed 2:2 breathing pattern than with the inversed ratio ventilation (both inspiratory:expiratory ratio 1:1).Conclusions: The marathoners’ breathing pattern may be a novel method to provide protection against ventilator-induced lung injury in clinical settings.

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Effects of melatonin in an experimental model of ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90211.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. L820-L827 ◽

Cited By ~ 24

Author(s):

Paula R. Pedreira ◽

Emilio García-Prieto ◽

Diego Parra ◽

Aurora Astudillo ◽

Elena Diaz ◽

...

Keyword(s):

Oxidative Stress ◽

Matrix Metalloproteinases ◽

Lung Injury ◽

Weight Ratio ◽

Peak Inspiratory Pressure ◽

Lung Damage ◽

Inspiratory Pressure ◽

Ventilator Induced Lung Injury ◽

Tnf Α ◽

Anti Inflammatory

Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice ( n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O], and high-pressure ventilation (peak inspiratory pressure 25 cmH2O, PEEP 0 cmH2O). Each group was divided into two subgroups: eight animals were treated with melatonin (10 mg/kg ip, 30 min before the onset of ventilation) and the remaining eight with vehicle. After 2 h of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio, and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins IL-1β, IL-6, TNF-α, and IL-10, and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/anti-inflammatory cytokines, and matrix turnover, respectively. Ventilation with high pressures induced severe lung damage and release of TNF-α, IL-6, and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF-α, IL-1β, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress.

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Simultaneous Pretreatment of Aspirin and Omega-3 Fatty Acid Attenuates Nuclear Factor-κB Activation in a Murine Model with Ventilator-Induced Lung Injury

Nutrients ◽

10.3390/nu13072258 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2258

Author(s):

Won-Gun Kwack ◽

Yoon-Je Lee ◽

Eun-Young Eo ◽

Jin-Haeng Chung ◽

Jae-Ho Lee ◽

...

Keyword(s):

Mechanical Ventilation ◽

Fatty Acid ◽

Lung Injury ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Omega 3 ◽

Omega 3 Fatty Acid ◽

Ventilator Induced Lung Injury ◽

Sequential Administration ◽

Pretreated Group

Ventilator-induced lung injury (VILI) is an important critical care complication. Nuclear factor-κB (NF-κB) activation, a critical signaling event in the inflammatory response, has been implicated in the tracking of the lung injury. The present study aimed to determine the effect of simultaneous pretreatment with enteral aspirin and omega-3 fatty acid on lung injury in a murine VILI model. We compared the lung inflammation after the sequential administration of lipopolysaccharides and mechanical ventilation between the pretreated simultaneous enteral aspirin and omega-3 fatty acid group and the non-pretreatment group, by quantifying NF-κB activation using an in vivo imaging system to detect bioluminescence signals. The pretreated group with enteral aspirin and omega-3 fatty acid exhibited a smaller elevation of bioluminescence signals than the non-pretreated group (p = 0.039). Compared to the non-pretreated group, the pretreatment group with simultaneous enteral aspirin and omega-3 fatty acid showed reduced expression of the pro-inflammatory cytokine, tumor necrosis factor-α, in bronchoalveolar lavage fluid (p = 0.038). Histopathological lung injury scores were also lower in the pretreatment groups compared to the only injury group. Simultaneous pretreatment with enteral administration of aspirin and omega-3 fatty acid could be a prevention method for VILI in patients with impending mechanical ventilation therapy.

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Redox Balance and Cellular Inflammation in the Diaphragm, Limb Muscles, and Lungs of Mechanically Ventilated Rats

Anesthesiology ◽

10.1097/aln.0b013e3181c38bed ◽

2010 ◽

Vol 112 (2) ◽

pp. 384-394 ◽

Cited By ~ 12

Author(s):

Judith Marín-Corral ◽

Leticia Martínez-Caro ◽

José A. Lorente ◽

Marta de Paula ◽

Lara Pijuan ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Lung Injury ◽

Protein Adducts ◽

Organ Injury ◽

Mechanically Ventilated ◽

Ventilator Induced Lung Injury ◽

Cellular Inflammation ◽

Cell Counts ◽

Limb Muscles

Background High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung injury and systemic inflammation in animal models of ventilator-induced lung injury. The authors aimed to explore whether high VT mechanical ventilation per se induces early oxidative stress and inflammation in the diaphragm, limb muscles, and lungs of healthy rats exposed to ventilator-induced lung injury. Methods Protein carbonylation and nitration, antioxidants (immunoblotting), and inflammation (immunohistochemistry) were evaluated in the diaphragm, gastrocnemius, soleus, tibialis anterior, and lungs of mechanically ventilated healthy rats and in nonventilated control animals (n = 8/group) for 1 h, using two different strategies (moderate VT [VT = 9 ml/kg] and high VT [VT = 35 ml/kg]). Results The main findings are summarized as follows: compared with controls, (1) the diaphragms and gastrocnemius of high-VT rats exhibited a decrease in reactive carbonyls, (2) the soleus and tibialis of high- and moderate-VT rodents showed a reduction in reactive carbonyls and malondialdehyde-protein adducts, (3) the lungs of high-VT rats exhibited a significant rise in malondialdehyde-protein adducts, (4) the soleus and tibialis of both high- and moderate-VT rats showed a reduction in protein nitration, (5) the lungs of high- and moderate-VT rats showed a reduction in antioxidant enzyme levels, but not in the muscles, and (6) the diaphragms and gastrocnemius of all groups exhibited very low inflammatory cell counts, whereas the lungs of high-VT rats exhibited a significant increase in inflammatory infiltrates. Conclusions Although oxidative stress and inflammation increased in the lungs of rats exposed to high VT, the diaphragm and limb muscles exhibited a decline in oxidative stress markers and very low levels of cellular inflammation.

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Noninvasive and Invasive Ventilatory Support II

10.2310/7ccsp.8366 ◽

2018 ◽

Author(s):

Pauline K. Park ◽

Nicole L Werner ◽

Carl Haas

Keyword(s):

Mechanical Ventilation ◽

Respiratory Failure ◽

Lung Injury ◽

Acute Respiratory Failure ◽

Ventilatory Support ◽

Underlying Disease ◽

Protective Ventilation ◽

Lung Protective Ventilation ◽

Pulmonary Mechanics ◽

Ventilator Induced Lung Injury

Invasive and noninvasive ventilation are important tools in the clinician’s armamentarium for managing acute respiratory failure. Although these modalities do not treat the underlying disease, they can provide the necessary oxygenation and ventilatory support until the causal pathology resolves. Care must be taken as even appropriate application can cause harm. Knowledge of pulmonary mechanics, appreciation of the basic machine settings, and an understanding of how common and advanced modes function allows the clinician to optimally tailor support to the patient while limiting iatrogenic injury. This second chapter reviews indications for mechanical ventilation, routine management, troubleshooting, and liberation from mechanical ventilation This review contains 6 figures, 7 tables and 60 references Keywords: Mechanical ventilation, lung protective ventilation, sedation, ventilator-induced lung injury, liberation from mechanical ventilation

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Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses

International Journal of Molecular Sciences ◽

10.3390/ijms21218203 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8203 ◽

Cited By ~ 1

Author(s):

Dmitry V. Chistyakov ◽

Arina I. Nikolskaya ◽

Sergei V. Goriainov ◽

Alina A. Astakhova ◽

Marina G. Sergeeva

Keyword(s):

Hyaluronic Acid ◽

Inflammatory Responses ◽

Specific Inhibitor ◽

Acid Synthesis ◽

Interleukin 10 ◽

Ultra Performance Liquid Chromatography ◽

Necrosis Factor Alpha ◽

Inflammatory Stimuli ◽

Anti Inflammatory ◽

Ha Synthase

Astrocytes are glial cells that play an important role in neuroinflammation. Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of inflammatory signaling pathways are still largely unknown due to the ectodermal origin of astrocytes. Recently, we have shown that hyaluronic acid (HA) may form part of astrocyte inflammatory responses. Therefore, we tested 4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, as a possible regulator of LPS-mediated responses. Rat primary astrocytes were treated with LPS with and without 4-MU and gene expression levels of inflammatory (interleukins 1β, (IL-1β), 6, (IL-6), tumor necrosis factor alpha TNFα,) and resolution interleukin 10 (IL-10) markers were evaluated via real-time PCR and western blot. The release of cytokines and HA was determined by ELISA. Oxylipin profiles were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. Our data show that 4-MU (i) has anti-inflammatory effects in the course of TLR4 activation, decreasing the cytokines level TNFα, IL-6 and IL-1β and increasing IL-10, (ii) downregulates prostaglandin synthesis but not via cyclooxygenases COX-1 and COX-2 pathways, (iii) modulates HA synthesis and decreases LPS-induced HA synthase mRNA expression (HAS-1, HAS-2) but does not have an influence on HAS-3, HYAL1 and HYAL2 mRNAs; (iv) the effects of 4-MU are predominantly revealed via JNK but not p38, ERK mitogen-activated protein kinases (MAPKs) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways. For the first time, it is shown that 4-MU possesses the useful potential to regulate an inflammatory astrocyte response.

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