Linking lung function and inflammatory responses in ventilator-induced lung injury

2011 ◽  
Vol 300 (1) ◽  
pp. L112-L120 ◽  
Author(s):  
Vincenzo Cannizzaro ◽  
Zoltan Hantos ◽  
Peter D. Sly ◽  
Graeme R. Zosky
Keyword(s):  
Lung Function ◽  
Lung Injury ◽  
Tidal Volume ◽  
Lung Volume ◽  
Inflammatory Responses ◽  
Lung Mechanics ◽  
Forced Oscillation Technique ◽  
Ventilation Strategy ◽  
Ventilator Induced Lung Injury ◽  
Tnf Α

Despite decades of research, the mechanisms of ventilator-induced lung injury are poorly understood. We used strain-dependent responses to mechanical ventilation in mice to identify associations between mechanical and inflammatory responses in the lung. BALB/c, C57BL/6, and 129/Sv mice were ventilated using a protective [low tidal volume and moderate positive end-expiratory pressure (PEEP) and recruitment maneuvers] or injurious (high tidal volume and zero PEEP) ventilation strategy. Lung mechanics and lung volume were monitored using the forced oscillation technique and plethysmography, respectively. Inflammation was assessed by measuring numbers of inflammatory cells, cytokine (IL-6, IL-1β, and TNF-α) levels, and protein content of the BAL. Principal components factor analysis was used to identify independent associations between lung function and inflammation. Mechanical and inflammatory responses in the lung were dependent on ventilation strategy and mouse strain. Three factors were identified linking 1) pulmonary edema, protein leak, and macrophages, 2) atelectasis, IL-6, and TNF-α, and 3) IL-1β and neutrophils, which were independent of responses in lung mechanics. This approach has allowed us to identify specific inflammatory responses that are independently associated with overstretch of the lung parenchyma and loss of lung volume. These data provide critical insight into the mechanical responses in the lung that drive local inflammation in ventilator-induced lung injury and the basis for future mechanistic studies in this field.

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

2008 ◽  
Vol 108 (2) ◽  
pp. 261-268 ◽  
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.

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

2012 ◽  
Vol 302 (4) ◽  
pp. L370-L379 ◽  
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.

scholarly journals Impact of high tidal volume ventilation on surfactant metabolism and lung injury in infant rats

2020 ◽  
Vol 319 (3) ◽  
pp. L562-L575
Author(s):  
Susanne Wiegert ◽  
Francesco Greco ◽  
Philipp Baumann ◽  
Sven Wellmann ◽  
Paula Grest ◽  
...  
Keyword(s):  
Lung Function ◽  
Lung Injury ◽  
Tidal Volume ◽  
De Novo ◽  
Lamellar Body ◽  
High Tidal Volume ◽  
Critically Ill Children ◽  
Phospholipid Content ◽  
Forced Oscillation Technique ◽  
Infant Rats

The poorly understood tolerance toward high tidal volume (VT) ventilation observed in critically ill children and age-equivalent animal models may be explained by surfactant homeostasis. The aim of our prospective animal study was to test whether high VT with adequate positive end-expiratory pressure (PEEP) is associated with surfactant de novo synthesis and secretion, leading to improved lung function, and whether extreme mechanical ventilation affects intracellular lamellar body formation and exocytosis. Rats (14 days old) were allocated to five groups: nonventilated controls, PEEP 5 cmH2O with VT of 8, 16, and 24 mL/kg, and PEEP 1 cmH2O with VT 24 mL/kg. Following 6 h of ventilation, lung function, surfactant proteins and phospholipids, and lamellar bodies were assessed by forced oscillation technique, quantitative real-time polymerase chain reaction, mass spectrometry, immunohistochemistry, and transmission electron microscopy. High VT (24 mL/kg) with PEEP of 5 cmH2O improved respiratory system mechanics and was not associated with lung injury, elevated surfactant protein expression, or surfactant phospholipid content. Extreme ventilation with VT 24 mL/kg and PEEP 1 cmH2O produced a mild inflammatory response and correlated with higher surfactant phospholipid concentrations in bronchoalveolar lavage fluid without affecting lamellar body count and morphology. Elevated phospholipid concentrations in the potentially most injurious strategy (VT 24 mL/kg, PEEP 1 cmH2O) need further evaluation and might reflect accumulation of biophysically inactive small aggregates. In conclusion, our data confirm the resilience of infant rats toward high VT-induced lung injury and challenge the relevance of surfactant synthesis, storage, and secretion as protective factors.

scholarly journals Regional tidal lung strain in mechanically ventilated normal lungs

2016 ◽  
Vol 121 (6) ◽  
pp. 1335-1347 ◽  
Author(s):  
Luis Felipe Paula ◽  
Tyler J. Wellman ◽  
Tilo Winkler ◽  
Peter M. Spieth ◽  
Andreas Güldner ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Lung Volume ◽  
Mechanically Ventilated ◽  
Reference Volume ◽  
Ventilator Induced Lung Injury ◽  
Vertical Heterogeneity ◽  
Dorsal Axis ◽  
Lung Strain ◽  
Normal Lungs

Parenchymal strain is a key determinant of lung injury produced by mechanical ventilation. However, imaging estimates of volumetric tidal strain (ε = regional tidal volume/reference volume) present substantial conceptual differences in reference volume computation and consideration of tidally recruited lung. We compared current and new methods to estimate tidal volumetric strains with computed tomography, and quantified the effect of tidal volume (VT) and positive end-expiratory pressure (PEEP) on strain estimates. Eight supine pigs were ventilated with VT = 6 and 12 ml/kg and PEEP = 0, 6, and 12 cmH2O. End-expiratory and end-inspiratory scans were analyzed in eight regions of interest along the ventral-dorsal axis. Regional reference volumes were computed at end-expiration (with/without correction of regional VT for intratidal recruitment) and at resting lung volume (PEEP = 0) corrected for intratidal and PEEP-derived recruitment. All strain estimates demonstrated vertical heterogeneity with the largest tidal strains in middependent regions ( P < 0.01). Maximal strains for distinct estimates occurred at different lung regions and were differently affected by VT-PEEP conditions. Values consistent with lung injury and inflammation were reached regionally, even when global measurements were below critical levels. Strains increased with VT and were larger in middependent than in nondependent lung regions. PEEP reduced tidal-strain estimates referenced to end-expiratory lung volumes, although it did not affect strains referenced to resting lung volume. These estimates of tidal strains in normal lungs point to middependent lung regions as those at risk for ventilator-induced lung injury. The different conditions and topography at which maximal strain estimates occur allow for testing the importance of each estimate for lung injury.

scholarly journals High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury

2003 ◽  
Vol 95 (4) ◽  
pp. 1385-1393 ◽  
Author(s):  
Michael R. Wilson ◽  
Sharmila Choudhury ◽  
Michael E. Goddard ◽  
Kieran P. O'Dea ◽  
Andrew G. Nicholson ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Tidal Volume ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
High Tidal Volume ◽  
Lung Pathology ◽  
Ventilator Induced Lung Injury ◽  
Tnf Α

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 ± 2.9 ml/kg, mean ± SD) for a duration of 156 ± 17 min until mean blood pressure fell below 45 mmHg ( series 1); high Vt for 120 min ( series 2); or low Vt (8.8 ± 0.5 ml/kg) for 120 or 180 min ( series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-α in lung lavage fluid at the early stage of injury ( series 2) but not the later stage ( series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-α by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-α and MIP-2 proteins and TNF-α bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-α and MIP-2 expression in mice. The apparently transient nature of TNF-α upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.

3-methyadenine inhibits lipopolysaccharides-induced pulmonary inflammation at the early stage of silicosis via blocking NF-κB signaling pathway

2021 ◽  
pp. 074823372110394
Author(s):  
Yujing Zhang ◽  
Shuai Huang ◽  
Shiyi Tan ◽  
Mingke Chen ◽  
Shang Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Late Stage ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Early Stage ◽  
Pulmonary Inflammation ◽  
Mechanism Study ◽  
Silica Dust ◽  
Tnf Α

Occupational exposure to silica dust is related to pulmonary inflammation and silicosis. Lipopolysaccharides (LPSs) could aggravate apoptosis in alveolar macrophages (AMs) of human silicosis through autophagy, yet how the reduction of autophagy attenuated LPS-induced lung injury and the related mechanisms need to be investigated. In the study, we aim to understand the role of 3-methyladenine (3-MA), an inhibitor of autophagy, in LPS-mediated inflammatory responses and fibrosis. We collected AMs from observers/silicosis patients. The results showed that LPS induced NF-κB-related pulmonary inflammation in observers and silicosis patients, as confirmed by an increase in the expression of IL-1β, IL-6, TNF-α, and p65, which could be inhibited by 3-MA treatment. In mice models, at the early stage (7d) of silicosis, but not the late (28d) stage, blocking autophagy reversed the increased levels of IL-1β, IL-6, TNF-α, and p65 caused by LPS. Mechanism study revealed that LPS triggered the expression of LC3 II, p62, and cleaved caspase-3 at the early stage exposed to silica, which could be restored by 3-MA, while there was no difference in the expression of LAMP1 either at the early or late stage of silicosis in different groups. Similarly, 3-MA treatment did not prevent fibrosis characterized by destroyed alveoli, collagen deposition, and increased expression of α-SMA and Col-1 induced by LPS at the late stage of silicosis. The results suggested that 3-MA has a role in the protection of lung injury at the early stage of silicosis and provided an experimental basis for preventive strategies of pulmonary inflammation and silicosis.

Lung mechanics are both dose and tidal volume dependant in LPS-induced lung injury

2009 ◽  
Vol 167 (3) ◽  
pp. 333-340 ◽  
Author(s):  
Dani-Louise Dixon ◽  
Hilde R. De Smet ◽  
Andrew D. Bersten
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Lung Mechanics

scholarly journals Resolvin D1 Alleviates Ventilator-Induced Lung Injury in Mice by Activating PPARγ/NF-κB Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Haifa Xia ◽  
Jingxu Wang ◽  
Shujun Sun ◽  
Fuquan Wang ◽  
Yiyi Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protective Effect ◽  
Tidal Volume ◽  
Signaling Pathways ◽  
Lung Tissue ◽  
Fatty Acid Derivative ◽  
High Tidal Volume ◽  
Treatment Modalities ◽  
Resolvin D1 ◽  
Ventilator Induced Lung Injury

As one of the basic treatment modalities in the intensive care unit (ICU), mechanical ventilation can cause or aggravate acute lung injury or ventilator-induced lung injury (VILI). Resolvin D1 (RvD1) is an endogenous polyunsaturated fatty acid derivative with strong anti-inflammatory action. In this study, we explored if RvD1 possesses a protective effect on VILI. Mice were ventilated with high tidal volume (40 mL/kg, HVT) for 4 h and were then intraperitoneally administered RvD1 at the beginning of high tidal volume ventilation and given GW9662 (a PPAR-γ antagonist) intraperitoneally 30 min before ventilation. RvD1 attenuated VILI, as evidenced by improved oxygenation and reduced histological injury, compared with HVT -induced lung injury. Similarly, it could ameliorate neutrophil accumulation and production of proinflammatory cytokines in lung tissue. In contrast, the protective effect of RvD1 on lung tissue could be reversed by GW9662. RvD1 mitigated VILI by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibiting nuclear factor-kappa B (NF-κB) signaling pathways in mice. In conclusion, RvD1 could reduce the inflammatory response in VILI by activating PPAR-γ and inhibiting NF-κB signaling pathways.

scholarly journals LncRNA HOTAIR Increases Inflammatory Responses by Activating NF-κB Pathway in LPS-Induced Acute Lung Injury

2020 ◽  
Author(s):  
XiaoMei Huang ◽  
ZeXun Mo ◽  
YuJun Li ◽  
Hua He ◽  
KangWei Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Noncoding Rna ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
A549 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Qrt Pcr ◽  
Tnf Α ◽  
Lncrna Hotair

Abstract Background Nuclear factor kappa-B (NF-κB) activation increased the expression of cytokines and further lead to lung injury was considered the main mechanism of acute lung injury (ALI). Here, we focus on exploring the potential regulatory mechanism between long noncoding RNA (LncRNA) HOX transcript antisense RNA (HOTAIR) and NF-κB on LPS-induced ALI. Methods A549 cells were then divided into 4 groups: HOTAIR group, NC group, si-HOTAIR group and si-NC group. These 4 groups were then treated with 1μg/mL lipopolysaccharides (LPS) or without LPS at 37°C for 24 h. The expression level of cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) and LncRNA HOTAIR were evaluated by quantitative Real Time Polymerase Chain Reaction (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA). Western Blot analysis was adopted for evaluating the level of p-IκBα/IκBα and p-p65/p65. Nuclear translocation of p65 was observed by immunofluorescence staining. Results qRT-PCR and ELISA assay showed that the expression of cytokines (IL-1β, IL-6 and TNF-α) and inflammatory gene HOTAIR was remarkably increased with LPS treatment (p < 0.01). Over-expression of HOTAIR significantly increased the expression of cytokines (including IL-1β, IL-6 and TNF-α) and NF-κB pathway associated proteins (including p-IκBα/IκBα and p-p65/p65), while knockdown of HOTAIR had the opposite effect (p < 0.01). The immunofluorescence assay showed that the level of p65 in the nucleus was significantly higher in the HOTAIR group and significantly lowers in the si-HOTAIR group (p < 0.01). Conclusion HOTAIR may play a pro-inflammatory response through NF-κB pathway in LPS-induced ALI, which may provide a perspective for further understanding the pathogenic mechanism of ALI.

scholarly journals Magnetic resonance imaging provides sensitive in vivo assessment of experimental ventilator-induced lung injury

2016 ◽  
Vol 311 (2) ◽  
pp. L208-L218 ◽  
Author(s):  
Dean O. Kuethe ◽  
Piotr T. Filipczak ◽  
Jeremy M. Hix ◽  
Andrew P. Gigliotti ◽  
Raúl San José Estépar ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Lung Injury ◽  
Real Time ◽  
Critical Role ◽  
Lung Mechanics ◽  
Therapeutic Effects ◽  
Resonance Imaging ◽  
Ventilator Induced Lung Injury

Animal models play a critical role in the study of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). One limitation has been the lack of a suitable method for serial assessment of acute lung injury (ALI) in vivo. In this study, we demonstrate the sensitivity of magnetic resonance imaging (MRI) to assess ALI in real time in rat models of VILI. Sprague-Dawley rats were untreated or treated with intratracheal lipopolysaccharide or PBS. After 48 h, animals were mechanically ventilated for up to 15 h to induce VILI. Free induction decay (FID)-projection images were made hourly. Image data were collected continuously for 30 min and divided into 13 phases of the ventilatory cycle to make cinematic images. Interleaved measurements of respiratory mechanics were performed using a flexiVent ventilator. The degree of lung infiltration was quantified in serial images throughout the progression or resolution of VILI. MRI detected VILI significantly earlier (3.8 ± 1.6 h) than it was detected by altered lung mechanics (9.5 ± 3.9 h, P = 0.0156). Animals with VILI had a significant increase in the Index of Infiltration ( P = 0.0027), and early regional lung infiltrates detected by MRI correlated with edema and inflammatory lung injury on histopathology. We were also able to visualize and quantify regression of VILI in real time upon institution of protective mechanical ventilation. Magnetic resonance lung imaging can be utilized to investigate mechanisms underlying the development and propagation of ALI, and to test the therapeutic effects of new treatments and ventilator strategies on the resolution of ALI.

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