Chemical pneumonitis secondary to accidental pulmonary polyethylene glycol-electrolyte solution infusion in a cat.

Newborn Respiratory Disorders

S1P lyase inhibition prevents lung injury following high pressure-controlled mechanical ventilation in aging mice

Sir, Diesel oil aspiration is an uncommon mode of hydrocarbon aspiration and can lead to severe chemical pneumonitis either due to direct inhalation of aerosol or aspiration of liquid or indirectly following aspiration of vomitus secondary to diesel oil ingestion during the manual siphoning from fuel tanks. Siphonage of fuel from the motor vehicles fuel tanks is a typical practice seen in third world countries. Data are sparse on outcomes and complications of direct diesel oil aspiration following manual siphoning.[12] We report a case of 21-year-old male industrial worker who was admitted to the emergency room with a history of diesel oil ingestion and aspiration following accidental siphoning of oil. He was febrile, dyspneic with altered sensorium and having feeble pulse (pulse rate-124/min) and falling blood pressure (82/40 mmHg). On auscultation of chest, coarse, basal, inspiratory crepitations were heard. Arterial blood gas (ABG) analysis showed severe hypoxemia with metabolic acidosis. In view of deteriorating clinical condition, his trachea was intubated with endotracheal tube and was supported with intravenous fluids and inotropes. He was then shifted to intensive care unit (ICU) for mechanical ventilatory support and further management. In ICU, chest X-ray Anteroposterior view (AP) showed bilateral, non-segmental, homogeneous opacities in the lower zones. There was a significant increase in leukocyte counts (total leukocyte count-16,200/Ul, neutrophills 92%). Empirical broad spectrum antibiotics (piperacillin/tazobactam 4.5 g IV q8h) were immediately started after sending blood and tracheal aspirate for culture and sensitivity. On day 2 in ICU, the patient's clinical condition deteriorated dramatically. Chest X-ray showed bilateral progression of infiltrates involving nearly all lobes of the lungs. ABG analysis showed severely diminished PF ratio (PaO2/ FIO2 < 100). These findings were suggestive of a severe form of acute respiratory distress syndrome (ARDS).[3] Aggressive supportive therapy and low tidal volume ventilation strategy was immediately initiated.[4] We also started a continuous infusion of low dose methylprednisolone (@ 1 mg/kg/day after giving bolus of 1 mg/kg IV). On day 5, he had an episode of pulseless ventricular tachyarrhythmia, unresponsive to all possible resuscitative measures and eventually expired that day. Direct aspiration of hydrocarbons may cause severe chemical (lipoidal) pneumonitis with perilous outcome.[25] The severity of lung tissue damage depends on physical characteristics of hydrocarbon, which includes viscosity, volatility and side chains of hydrocarbons. The probability of severe lung affliction is extensive with hydrocarbons having high volatility and low viscosity (<60 saybolts seconds universal (SSU)).[6] Diesel fuel (grade 1D and 2D) have a low viscosity (32-45 SSU) and is highly volatile and a potential hydrocarbon to cause severe progressive lung damage and fatal ARDS.[6] In early period of hydrocarbon induced pneumonia, patients may have non-specific symptoms such as cough, breathlessness and rarely chest pain or haemoptysis.[7] Later, these patients may develop cardiomyopathies or fatal cardiac arrhythmias.[7] Although right middle lobes are commonly affected by direct aspiration of diesel, chest radiographic findings may include consolidation, atelectasis, pleural effusion and lower lobe involvement as seen in this patient.[128] The management strategies in these patients are usually symptomatic and supportive. There is limited and controversial role of corticosteroids and antibiotics with sparse data on outcomes.[18] This patient showed accelerated deterioration of lung functions and eventually expired due to fatal cardiac arrhythmias within a period of 4 days despite initiating corticosteroids, broad-spectrum antibiotics and strict adherence to ventilator protocols followed in ARDS patients.[4] This case highlights that chemical pneumonitis triggered by direct diesel oil aspiration following manual siphoning is a pernicious clinical condition in which lung damage is progressive and extensive resulting in ARDS, which seldom respond to standard management strategies. Moreover, death can ensue due to fatal cardiac arrhythmias even in early course of the disease. Critical carers should circumspect this rare and fatal clinical condition early in its course and should intervene with aggressive management strategies to avoid cataclysmic outcomes.

Background: Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in a pathological state such as sepsis. This pathological process is known as the "two-hit" theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. The second hit occurs when MV is applied to lung tissue in a fragile state, and it is noteworthy that this MV is harmless to healthy lung tissue, further aggravating preexisting lung injury through unknown mechanisms. This interaction between initial injury and subsequent MV develops a malignant cycle significantly exacerbating lung injury and severely hampering patient prognosis. The two-hit theory is critical to understanding the complicated mechanisms of ventilator-associated lung injury and facilitates the subsequent development of targeted therapeutic strategies. Methods and Results: The cecum ligation and perforation mice model was used to mimic clinical sepsis patients. After 12 h, the mice were mechanically ventilated for 2 to 6 h. MV by itself did not lead to HMGB1 release, but significantly strengthened HMGB1 in plasma and cytoplasm of lung tissue in septic mice. Plasma and lung tissue activation of cytokines and chemokines, mitogen-activated protein kinase signaling pathway, neutrophil recruitment, and acute lung injury were progressively decreased in LysM HMGB1 -/- (Hmgb1 deletion in myeloid cells) and iHMGB1 -/- mice (inducible HMGB1 -/- mouse strain where the Hmgb1 gene was globally deleted after tamoxifen treatment). Compared with C57BL/6 mice, although EC-HMGB1 -/- (Hmgb1 deletion in endothelial cells) mice did not have lower levels of inflammation, neutrophil recruitment and lung injury were reduced. Compared with LysM HMGB1 -/- mice, EC-HMGB1 -/- mice had higher levels of inflammation but significantly lower neutrophil recruitment and lung injury. Overall, iHMGB1 -/- mice had the lowest levels of all the above indicators. The level of inflammation, neutrophil recruitment, and the degree of lung injury were decreased in RAGE -/- mice, and even the above indices were further decreased in TLR4/RAGE -/- mice. Levels of inflammation and neutrophil recruitment were decreased in caspase-11 -/- and caspase-1/11 -/- mice, but there was no statistical difference between these two gene knockout mice. Conclusions: These data show for the first time that the caspase-1/caspase-11-HMGB1-TLR4/RAGE signaling pathway plays a key role in mice model of sepsis-induced lung injury exacerbated by MV. Different species of HMGB1 knockout mice have different lung-protective mechanisms in the two-hit model, and location is the key to function. Specifically, LysM HMGB1 -/- mice due to the deletion of HMGB1 in myeloid cells resulted in a pulmonary-protective mechanism that was associated with a downregulation of the inflammatory response. EC-HMGB1 -/- mice are deficient in HMGB1 owing to endothelial cells, resulting in a distinct pulmonary-protective mechanism independent of the inflammatory response and more relevant to the improvement of alveolar-capillary permeability. iHMGB1 -/- mice, which are systemically HMGB1-deficient, share both of these lung-protective mechanisms.

Activation of NFkB and coagulation in lung injury by hyperoxia and excessive mechanical ventilation: one more reason “low and slow” is the way to go?

Increased lung heterogeneity from regional alveolar collapse drives ventilator-induced lung injury in patients with acute respiratory distress syndrome (ARDS). New methods of preventing this injury require study. Our study objective was to determine whether the combination of temporary transvenous diaphragm neurostimulation (TTDN) with standard-of-care volume-control mode ventilation changes lung mechanics, reducing ventilator-induced lung injury risk in a preclinical ARDS model. Moderate ARDS was induced using oleic acid administered into the pulmonary artery in pigs, which were ventilated for 12 h postinjury using volume-control mode at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH2O, with respiratory rate and [Formula: see text] set to achieve normal arterial blood gases. Two groups received TTDN, either every second breath [mechanical ventilation (MV) + TTDN50%, n = 6] or every breath (MV + TTDN100%, n = 6). A third group received volume-control ventilation only (MV, n = 6). At study-end, [Formula: see text]/[Formula: see text] was highest and alveolar-arterial oxygen (A-a) gradient was lowest for MV + TTDN100% (P < 0.05). MV + TTDN100% had the smallest end-expiratory lung volume loss and lowest extravascular lung water at study-end (P < 0.05). Static lung compliance was highest and transpulmonary driving pressure was lowest at baseline, postinjury, and study-end in MV + TTDN100% (P < 0.05). The total exposure to transpulmonary driving pressure, mechanical power, and mechanical work was the lowest in MV + TTDN100% (P < 0.05). Lung injury score and total inflammatory cytokine concentration in lung tissue were the lowest in MV + TTDN100% (P < 0.05). Volume-control ventilation plus transvenous diaphragm neurostimulation on every breath improved [Formula: see text]/[Formula: see text], A-a gradient, and alveolar homogeneity, as well as reduced driving pressure, mechanical power, and mechanical work, and resulted in lower lung injury scores and tissue cytokine concentrations in a preclinical ARDS model.NEW & NOTEWORTHY Combining temporary transvenous diaphragm neurostimulation with volume-control ventilation on every breath, called negative-pressure-assisted ventilation, improved gas exchange and alveolar homogeneity in a preclinical model of moderate ARDS. Transpulmonary driving pressure, mechanical power, and mechanical work reductions were observed and resulted in lower lung injury scores and tissue cytokine concentrations in the every-breath-neurostimulation group compared with volume-control ventilation only. Negative-pressure-assisted ventilation is an exciting new potential tool to reduce ventilator-induced lung injury in patients with ARDS.

Mechanical ventilation can induce lung injury and exacerbate brain injury due to lung-brain interaction. The current study sought to investigate the mechanism of lung-brain interaction induced by mechanical ventilation and offer theoretical insight into the management of ventilator-induced brain injury. The experimental mice were assigned into the spontaneously breathing group and the mechanical ventilation group and injected with dopamine (DA) receptor antagonist haloperidol or P2Y1 receptor antagonist MRS2279 before ventilation. In vitro assay was conducted using lung epithelial cells MLE-12 hippocampal neuron cells and HT-22. Mouse recognition function and lung injury were examined. The condition and concentration of neurons in the hippocampus were observed. The levels of several inflammatory factors, DA, adenosine triphosphate (ATP), P2Y1R, and dysbindin-1 were detected. Mechanical ventilation induced lung and brain injury in mice, manifested in increased inflammatory factors in the bronchoalveolar lavage fluid and hippocampus, prolonged escape latency, and swimming distance and time in the target quadrant with a weakened concentration of neurons in the hippocampus. Our results presented elevated ATP and P2Y1R expressions in the mechanically ventilated mice and stretched MLE-12 cells. The mechanically ventilated mice and P2Y1 receptor activator MRS2365-treated HT-22 cells presented with elevated levels of DA and dysbindin-1. Inactivation of P2Y1 receptor in the hippocampus or blockage of DA receptor alleviated brain injury induced by mechanical ventilation in mice. To conclude, the current study elicited that lung injury induced by mechanical ventilation exacerbated brain injury in mice by increasing ATP production, activating the P2Y1 receptor, and thus promoting DA release.

BackgroundPreventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation.MethodsPlasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation.ResultsPlasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed.ConclusionPlasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.

Patients who experience severe trauma are at increased risk for the development of acute lung injury and acute respiratory distress syndrome. The management strategies used to treat respiratory failure in this patient population should be comprehensive. Current trends in the management of acute lung injury and acute respiratory distress syndrome consist of maintaining acceptable gas exchange while limiting ventilator-associated lung injury. Currently, two distinct forms of ventilator-associated lung injury are recognized to produce alveolar stress failure and have been termed low-volume lung injury (intratidal alveolar recruitment and derecruitment) and high-volume lung injury (alveolar stretch and overdistension). Pathologically, alveolar stress failure from low- and high-volume ventilation can produce lung injury in animal models and is termed ventilator-induced lung injury. The management goal in acute lung injury and acute respiratory distress syndrome challenges clinicians to achieve the optimal balance that both limits the forms of alveolar stress failure and maintains effective gas exchange. The integration of new ventilator modes that include the augmentation of spontaneous breathing during mechanical ventilation may be beneficial and may improve the ability to attain these goals. Airway pressure release ventilation is a mode of mechanical ventilation that maintains lung volume to limit intra tidal recruitment /derecruitment and improves gas exchange while limiting over distension. Clinical and experimental data demonstrate improvements in arterial oxygenation, ventilation-perfusion matching (less shunt and dead space ventilation), cardiac output, oxygen delivery, and lower airway pressures during airway pressure release ventilation. Mechanical ventilation with airway pressure release ventilation permits spontaneous breathing throughout the entire respiratory cycle, improves patient comfort, reduces the use of sedation, and may reduce ventilator days.

BackgroundPrevious studies have demonstrated that exposure to nickel nanoparticles (Nano-Ni) causes oxidative stress and severe, persistent lung inflammation, which are strongly associated with pulmonary toxicity. However, few studies have investigated whether surface modification of Nano-Ni could alter Nano-Ni-induced lung injury, inflammation, and fibrosis in vivo. Here, we propose that alteration of physicochemical properties of Nano-Ni through modification of Nano-Ni surface may change Nano-Ni-induced lung injury, inflammation, and fibrosis.MethodsAt first, dose–response and time-response studies were performed to observe lung inflammation and injury caused by Nano-Ni. In the dose–response studies, mice were intratracheally instilled with 0, 10, 20, 50, and 100 μg per mouse of Nano-Ni and sacrificed at day 3 post-exposure. In the time-response studies, mice were intratracheally instilled with 50 µg per mouse of Nano-Ni and sacrificed at days 1, 3, 7, 14, 28, and 42 post-instillation. At the end of the experiment, mice were bronchoalveolar lavaged (BAL) and the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BAL fluid (BALF) were determined. In the comparative studies, mice were intratracheally instilled with 50 μg per mouse of Nano-Ni or with the same molar concentration of Ni as Nano-Ni of either partially [O]-passivated Nano-Ni (Nano-Ni–P) or carbon-coated Nano-Ni (Nano-Ni–C). At day 3 post-exposure, BAL was performed and the above cellular and biochemical parameters in the BALF were analyzed. The MMP-2/9 protein levels and activities in the BALF and mouse lung tissues were also determined. Mouse lung tissues were also collected for H&E staining, and measurement of thiobarbituric acid reactive substances (TBARS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the genomic DNA. At day 42 post-exposure, mouse right lung tissues were collected for H&E and Trichrome stainings, and left lung tissues were collected to determine the hydroxyproline content.ResultsExposure of mice to Nano-Ni resulted in a dose–response increase in acute lung inflammation and injury reflected by increased neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF. The time-response study showed that Nano-Ni-induced acute lung inflammation and injury appeared as early as day 1, peaked at day 3, and attenuated at day 7 post-instillation. Although the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF dramatically decreased over the time, their levels were still higher than those of the controls even at day 42 post-exposure. Based on the results of the dose- and time-response studies, we chose a dose of 50 µg per mouse of Nano-Ni, and day 3 post-exposure as short-term and day 42 post-exposure as long-term to compare the effects of Nano-Ni, Nano-Ni–P, and Nano-Ni–C on mouse lungs. At day 3 post-exposure, 50 μg per mouse of Nano-Ni caused acute lung inflammation and injury that were reflected by increased neutrophil count, CXCL1/KC level, LDH activity, concentration of total protein, and MMP-2/9 protein levels and activities in the BALF. Nano-Ni exposure also caused increased MMP-2/9 activities in the mouse lung tissues. Histologically, infiltration of large numbers of neutrophils and macrophages in the alveolar space and interstitial tissues was observed in mouse lungs exposed to Nano-Ni. Nano-Ni–P exposure caused similar acute lung inflammation and injury as Nano-Ni. However, exposure to Nano-Ni–C only caused mild acute lung inflammation and injury. At day 42 post-exposure, Nano-Ni caused extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa and alveolar space. Lung fibrosis was also observed in Nano-Ni–P-exposed lungs, but to a much lesser degree. Only slight or no lung fibrosis was observed in Nano-Ni–C-exposed lungs. Nano-Ni and Nano-Ni–P, but not Nano-Ni–C, caused significantly elevated levels of TBARS in mouse lung tissues and 8-OHdG in mouse lung tissue genomic DNA, suggesting that Nano-Ni and Nano-Ni–P induce lipid peroxidation and oxidative DNA damage in mouse lung tissues, while Nano-Ni–C does not.ConclusionOur results demonstrate that short-term Nano-Ni exposure causes acute lung inflammation and injury, while long-term Nano-Ni exposure causes chronic lung inflammation and fibrosis. Surface modification of Nano-Ni alleviates Nano-Ni-induced pulmonary effects; partially passivated Nano-Ni causes similar effects as Nano-Ni, but the chronic inflammation and fibrosis were at a much lesser degree. Carbon coating significantly alleviates Nano-Ni-induced acute and chronic lung inflammation and injury.

Objective To evaluate the effect of high-frequency oscillatory ventilation (HFOV) on lung injury in the piglets with acute respiratory distress syndrome (ARDS). Methods Twelve male piglets, aged 6-8 weeks, weighing 14-16 kg, were randomly divided into 2 groups (n=6 each)using a random number table: conventional mechanical ventilation with low tidal volume group (CMV group) and HFOV group.ARDS was induced by bilateral pulmonary lavages with isotonic saline (38 ℃), repeated every 10 min until the oxygenation index<200 mmHg.After successful establishment of the model, CMV group was ventilated using conventional mechanical ventilation with low tidal volumes.After successful establishment of the model, HFOV group was ventilated using HFOV, lung recruitment was performed, the airway pressure was set at 25 cmH2O and maintained at this level for 30 s, and the airway pressure was then adjusted 5 cmH2O higher than that after successful establishment of the model, with bias flow 25 L/min, inspiratory time ratio 33%, frequency 8 Hz, amplitude 40-80 cmH2O, and inspiratory oxygen fraction 1.0.In both groups, carbon dioxide partial pressure was maintained between 35 and 50 mmHg.Before establishment of the model (baseline), after successful establishment of the model (T1), and at 0.5, 1.0, 2.0 and 4.0 h after beginning of mechanical ventilation (T2-5), blood samples were collected from the femoral artery and central vein for blood gas analysis, arterial oxygen partial pressure and carbon dioxide partial pressure were recorded, oxygen delivery index, oxygen consumption index, oxygenation index and intrapulmonary shunt were calculated, and the improvement in pulmonary function (oxygenation index≥200 mmHg) was recorded.At T0, T1 and T5, venous blood samples were collected for determination of the concentrations of serum Clara cell secretory protein 16, soluble intercellular adhesion molecule-1, and high-mobility group box 1. Results Compared with CMV group, the arterial oxygen partial pressure at T3-5 and oxygenation index at T4, 5 were significantly increased (P 0.05). Conclusion Compared with conventional mechanical ventilation with low tidal volumes, although HFOV improves lung oxygenation, the degree is small in the piglets with ARDS. Key words: High-frequency ventilation; Respiratory distress syndrome, adult

Supplemental oxygen is a life‐saving intervention provided to individuals suffering from respiratory distress, including adults with acute respiratory distress syndrome (ARDS) as well as premature newborns with respiratory distress syndrome. However, experimental evidence has shown that supplemental oxygen can create a hyperoxic environment which can lead to and exacerbate existing pulmonary injury due to increases in pathogenic reactive oxygen species (ROS) and oxidative stress. Many molecular and biochemical mechanisms are known to regulate ROS levels and oxidative stress, but previous studies have shown the importance of cytochrome P450 1A1 and 1A2 (CYP1A1/1A2) as well as the aryl hydrocarbon receptor (AHR) in the protection against hyperoxic lung injury. Further, there is evidence suggesting that cytochrome P450 1B1 (CYP1B1) may contribute to hyperoxic toxicity in human epithelial cells. The objective of this study was to test the hypothesis that CYP1B1 mechanistically contributes to hyperoxia‐induced toxicity. Ten‐week‐old C57BL/6 (WT) and Cyp1b1−/− male mice were exposed to hyperoxia (&gt;95% oxygen) for 24–72 hours or maintained in room air as a control group. Lung weight changes were used to quantify lung injury. Mass spectrometry and 32P‐postlabeling were used to quantify lipid peroxidation and oxidative DNA damage, respectively, as markers of oxidative stress. Western blot and qPCR were used to quantify CYP1 protein and RNA expression. We found that Cyp1b1−/− mice had significantly decreased normalized lung weights after 48 (P=0.04) and 72 hours (P=0.017) of hyperoxia exposure, indicating reduced pulmonary edema and lung injury. We also found that Cyp1b1−/− mice have lower pulmonary isofurans (P=0.0331) and oxidative DNA adducts (P=0.0157) after 24 hours of hyperoxia. Gene expression studies showed that Cyp1b1−/− mice had increased CYP1A1 (P=2.9×10‐05) RNA expression during hyperoxia exposure and increased CYP1A2 (P=0.016) RNA expression after 48 hours of hyperoxia. Our results support the hypothesis that CYP1B1 contributes to hyperoxic lung injury, possibly by increasing ROS levels and oxidative stress. Our results also suggest that Cyp1b1−/− mice display lesser lung injury in part via increased transcriptional activation of Cyp1a1/1a2 genes. The goal of future studies will be to determine if CYP1B1 directly contributes to injury by creating a pro‐oxidant environment or indirectly contributes to injury by negatively feeding back on protective AHR‐dependent transcription. Elucidating the mechanism underlying these observations will help determine the viability of CYP1B1‐directed therapeutics and treatment strategies to treat and/or prevent hyperoxia toxicity and improve care for ARDS patients.Support or Funding InformationResearch reported in this publication was supported by the National Institutes of Health under award number R01ES019689, R01ES009132, R01HL12516, R01HL129794, and R01HL087174 to B.M., R01HL088343 to X.I.C., and T32GM088129 to A.C.V. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Science, Medicine, and the Anesthesiologist

Does oxygen tune cellular mechanotransduction?

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1α, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-γ (PI3K-γ) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-γ pathway, regardless of endotoxemia. Wild-type or PI3K-γ-deficient C57BL/6 mice were exposed to 30 mL/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1α, PERK), morphological rearrangement, PI3K-γ expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-γ-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-γ pathway.