Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19.

Rationale: Alveolar and endothelial injury may be differentially associated with coronavirus disease (COVID-19) severity over time. Objectives: To describe alveolar and endothelial injury dynamics and associations with COVID-19 severity, cardiorenovascular injury, and outcomes. Methods: This single-center observational study enrolled patients with COVID-19 requiring respiratory support at emergency department presentation. More than 40 markers of alveolar (including receptor for advanced glycation endproducts [RAGE]), endothelial (including angiopoietin-2), and cardiorenovascular injury (including renin, kidney injury molecule-1, and troponin-I) were serially compared between invasively and spontaneously ventilated patients using mixed-effects repeated-measures models. Ventilatory ratios were calculated for intubated patients. Associations of biomarkers with modified World Health Organization scale at Day 28 were determined with multivariable proportional-odds regression. Measurements and Main Results: Of 225 patients, 74 (33%) received invasive ventilation at Day 0. RAGE was 1.80-fold higher in invasive ventilation patients at Day 0 (95% confidence interval [CI], 1.50-2.17) versus spontaneous ventilation, but decreased over time in all patients. Changes in alveolar markers did not correlate with changes in endothelial, cardiac, or renal injury markers. In contrast, endothelial markers were similar to lower at Day 0 for invasive ventilation versus spontaneous ventilation, but then increased over time only among intubated patients. In intubated patients, angiopoietin-2 was similar (fold difference, 1.02; 95% CI, 0.89-1.17) to nonintubated patients at Day 0 but 1.80-fold higher (95% CI, 1.56-2.06) at Day 3; cardiorenovascular injury markers showed similar patterns. Endothelial markers were not consistently associated with ventilatory ratios. Endothelial markers were more often significantly associated with 28-day outcomes than alveolar markers. Conclusions: Alveolar injury markers increase early. Endothelial injury markers increase later and are associated with cardiorenovascular injury and 28-day outcome. Alveolar and endothelial injury likely contribute at different times to disease progression in severe COVID-19.

LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.

Massive Vespa basalis stings induce an envenoming syndrome.

Envenoming syndrome induced by massive Vespa basalis stings is a critical condition. Severe systemic reaction may present with hemolytic activity and rhabdomyolysis, leading diffuse alveolar hemorrhage, adult respiratory distress syndrome, coagulopathy, and multiple organs failure. In severe envenoming syndrome population, extracorporeal membrane oxygenation (ECMO) may be considered for unstable hemodynamic status. However, few studies reported ECMO in venom-induced disseminated intravascular coagulation patients. Here, we provide a case presented with pulmonary hemorrhage due to multiple Vespa basalis stings tried to rescue by veno-arterial extracorporeal membrane oxygenation. We also highlight that early recognition of venom-induced disseminated intravascular coagulation by checking coagulation profile in high risk patients may prevent from poor outcome.

Biomarker profiles of coagulopathy and alveolar epithelial injury in acute respiratory distress syndrome with idiopathic/immune-related disease or common direct risk factors.

BACKGROUND: Altered coagulation and alveolar injury are the hallmarks of acute respiratory distress syndrome (ARDS). However, whether the biomarkers that reflect pathophysiology differ depending on the etiology of ARDS has not been examined. This study aimed to investigate the biomarker profiles of coagulopathy and alveolar epithelial injury in two subtypes of ARDS: patients with direct common risk factors (dARDS) and those with idiopathic or immune-related diseases (iARDS), which are classified as "ARDS without common risk factors" based on the Berlin definition. METHODS: This retrospective, observational study included adult patients who were admitted to the intensive care unit (ICU) at a university hospital with a diagnosis of ARDS with no indirect risk factors. Plasma biomarkers (thrombin-antithrombin complex [TAT], plasminogen activator inhibitor [PAI]-1, protein C [PC] activity, procalcitonin [PCT], surfactant protein [SP]-D, and KL-6) were routinely measured during the first 5 days of the patient's ICU stay. RESULTS: Among 138 eligible patients with ARDS, 51 were excluded based on the exclusion criteria (n = 41) or other causes of ARDS (n = 10). Of the remaining 87 patients, 56 were identified as having dARDS and 31 as having iARDS. Among the iARDS patients, TAT (marker of thrombin generation) and PAI-1 (marker of inhibited fibrinolysis) were increased, and PC activity was above normal. In contrast, PC activity was significantly decreased, and TAT or PAI-1 was present at much higher levels in dARDS compared with iARDS patients. Significant differences were also observed in PCT, SP-D, and KL-6 between patients with dARDS and iARDS. The receiver operating characteristic (ROC) analysis showed that areas under the ROC curve for PC activity, PAI-1, PCT, SP-D, and KL-6 were similarly high for distinguishing between dARDS and iARDS (PC 0.86, P = 0.33; PAI-1 0.89, P = 0.95; PCT 0.89, P = 0.66; and SP-D 0.88, P = 0.16 vs. KL-6 0.90, respectively). CONCLUSIONS: Coagulopathy and alveolar epithelial injury were observed in both patients with dARDS and with iARDS. However, their biomarker profiles were significantly different between the two groups. The different patterns of PAI-1, PC activity, SP-D, and KL-6 may help in differentiating between these ARDS subtypes.

Radiation-induced lung injury: impact on macrophage dysregulation and lipid alteration - a review.

Lung cancer continues to be the leading cause of cancer deaths and more than one million lung cancer patients will die every year worldwide. Radiotherapy (RT) plays an important role in lung cancer treatment, but the side effects of RT are pneumonitis and pulmonary fibrosis. RT-induced lung injury causes damage to alveolar-epithelial cells and vascular endothelial cells. Macrophages play an important role in the development of pulmonary fibrosis despite its role in immune response. These injury activated macrophages develop into classically activated M1 macrophage or alternative activated M2 macrophage. It secretes cytokines, interleukins, interferons, and nitric oxide. Several pro-inflammatory lipids and pro-apoptotic proteins cause lipotoxicity such as LDL, FC, DAG, and FFA. The overall findings in this review conclude the importance of macrophages in inducing toxic/inflammatory effects during RT of lung cancer, which is clinically vital to treat the radiation-induced fibrosis.

Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell Repair.

Studies showed that TRIM72 is essential for repair of alveolar cell membrane disruptions, and exogenous recombinant human TRIM72 protein (rhT72) demonstrated tissue-mending properties in animal models of tissue injury. Here we examine the mechanisms of rhT72-mediated lung cell protection in vitro and test the efficacy of inhaled rhT72 in reducing tissue pathology in a mouse model of ventilator-induced lung injury. In vitro lung cell injury was induced by glass beads and stretching. Ventilator-induced lung injury was modeled by injurious ventilation at 30 ml/kg tidal volume. Affinity-purified rhT72 or control proteins were added into culture medium or applied through nebulization. Cellular uptake and in vivo distribution of rhT72 were detected by imaging and immunostaining. Exogenous rhT72 maintains membrane integrity of alveolar epithelial cells subjected to glass bead injury in a dose-dependent manner. Inhaled rhT72 decreases the number of fatally injured alveolar cells, and ameliorates tissue-damaging indicators and cell injury markers after injurious ventilation. Using in vitro stretching assays, we reveal that rhT72 improves both cellular resilience to membrane wounding and membrane repair after injury. Image analysis detected rhT72 uptake by rat alveolar epithelial cells, which can be inhibited by a cholesterol-disrupting agent. In addition, inhaled rhT72 distributes to the distal lungs, where it colocalizes with phosphatidylserine detection on nonpermeabilized lung slices to label wounded cells. In conclusion, our study showed that inhaled rhT72 accumulates in injured lungs and protects lung tissue from ventilator injury, the mechanisms of which include improving cell resilience to membrane wounding, localizing to injured membrane, and augmenting membrane repair.

Predictors of diffuse alveolar damage in patients with acute respiratory distress syndrome: a retrospective analysis of clinical autopsies.

BACKGROUND: Although diffuse alveolar damage (DAD) is considered the typical histological pattern of acute respiratory distress syndrome (ARDS), only half of patients exhibit this morphological hallmark. Patients with DAD may have higher mortality than those without DAD. Therefore, we aimed to identify the factors associated with DAD in patients with ARDS. METHODS: We analyzed autopsy samples of 356 patients who had ARDS at the time of death. DAD was assessed by two pathologists, and ARDS criteria were evaluated by two intensivists. Criteria for severe ARDS included the degree of hypoxemia and the ancillary variables of the current Berlin definition assessed within 48 h before death: radiographic severity, high positive end-expiratory pressure (PEEP) level, and physiological variables (i.e., altered respiratory system compliance and large anatomic dead space). RESULTS: After multivariable analysis, high PEEP levels, physiological variables, and opacities involving only three quadrants on chest radiographs were not associated with DAD. The four markers independently associated with DAD were (1) duration of evolution (OR 3.29 [1.95-5.55] for patients with ARDS ≥ 3 days, p < 0.001), (2) degree of hypoxemia (OR 3.92 [1.48-10.3] for moderate ARDS and 6.18 [2.34-16.3] for severe ARDS, p < 0.01 for both), (3) increased dynamic driving pressure (OR 1.06 [1.04-1.09], p = 0.007), and (4) radiographic severity (OR 2.91 [1.47-5.75] for patients with diffuse opacities involving the four quadrants, p = 0.002). DAD was found in two-thirds of patients with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤ 100 mmHg and opacities involving the four quadrants. CONCLUSIONS: In addition to severe hypoxemia, diffuse opacities involving the four quadrants were a strong marker of DAD.

Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth.

BACKGROUND: Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. METHODS AND RESULTS: Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. CONCLUSIONS: Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.

Dexmedetomidine Attenuates Bilirubin-Induced Lung Alveolar Epithelial Cell Death In Vitro and In Vivo.

OBJECTIVE: To investigate bilirubin-induced lung alveolar epithelial cell injury together with the protection afforded by dexmedetomidine. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory. SUBJECTS: Sprague Dawley rats. INTERVENTIONS: Alveolar epithelial A549 cell lines were cultured and received bilirubin (from 0 to 160 µM) to explore the protective pathway of dexmedetomidine on bilirubin-induced alveolar epithelial cell injury assessed by immunochemistry and flow cytometry. Sprague-Dawley rats were subjected to common bile duct ligation surgery to explore the protective effect of dexmedetomidine on hyperbilirubinemia-induced alveolar epithelial cell injury and respiratory failure in comparison with the Sham (subjected to the surgery procedure but without bile duct ligation) or dexmedetomidine control (only received intraperitoneal injection of dexmedetomidine). MEASUREMENTS AND MAIN RESULTS: In vitro, dexmedetomidine reversed the collapse of mitochondrial membrane potential (Δψm), upregulation of cytochrome C, B cell leukemia 2 associated X protein, and cleaved-caspase 3 and 9 in A549 epithelial cells with bilirubin challenge. Furthermore, dexmedetomidine reversed the arrest of cell cycle and the downregulation of the transforming growth factorß, phosphorylated mammalian target of rapamycin, and p42/44 mitogen-activated protein kinase induced by bilirubin. In vivo, pulmonary edema and inflammation were found after common bile duct ligation. Bilirubin and PaCO2 were significantly increased, and oxygen (PaO2) was significantly decreased in the blood of common bile duct ligation rats from the postsurgery day 7 to day 21 when compared with those in the sham controls, respectively (p < 0.01). Daily intraperitoneal injection of dexmedetomidine significantly alleviated the lung edema and injury and prevented respiratory failure. CONCLUSION: Our data both in vitro and in vivo demonstrated that dexmedetomidine protected alveolar epithelial cell from bilirubin-induced injury. Dexmedetomidine may be a good choice of anesthetic/sedative for patients with chronic liver disease during the perioperative period.

Minute lesions of alveolar damage in lungs of patients with stable idiopathic pulmonary fibrosis.

AIMS: To investigate the mechanisms underlying the acute exacerbation of idiopathic pulmonary fibrosis, and in particular the role of minute lesions of alveolar damage. METHODS AND RESULTS: We examined surgical lung biopsy samples from 38 patients with stable idiopathic pulmonary fibrosis, and evaluated the association between the foci and development of acute exacerbation. Mild extravasation, probably resulting from lung injury and intra-alveolar oedema fluid, were observed in narrow areas of architecturally intact lung tissue. Minute lesions of alveolar damage were detected in these areas. Alveolar epithelial cells in these lesions were injured. Hypoxia-inducible factor-2α-positive macrophages, tumour necrosis factor-α-positive macrophages and neutrophils had accumulated in alveolar spaces in and around these lesions. Cases were classified into patients without (17) and with (21) minute lesions of alveolar damage. Development to acute exacerbation (five cases) occurred only in patients with minute lesions of alveolar damage (P = 0.03). CONCLUSIONS: The formation of minute lesions of alveolar damage may be initiated by hypoxia, and such lesions play important roles in the development of acute exacerbation.

A normobaric gas exposure animal chamber and its validation in hyperoxia exposure.

We are living in an environment full of gases, and any change in the concentration of a component of the air or contaminants (usually toxic) in the air may significantly threaten human health. Thus, to investigate the influence of gases in animal models it is helpful to elucidate the pathogenesis of gas-related injury. Although there are devices used for gas exposure in animals, there are still limitations in the establishment of these animal models, such as the change in gas concentration during the refreshing of water, food and litter, and the contamination of toxic gases released by animals. Herein, we freshly prepared a chamber for normobaric gas exposure. During the exposure in this chamber, the refreshing of water, food and litter does not require opening of the chamber. The chamber gases are continuously circulated and filtered, and the gas concentration remains very stable. To validate the feasibility of this chamber, rats were exposed to pure oxygen as an example. Results showed that rats with hyperoxia-induced lung injury simulated by pure oxygen exposure displayed the representative characteristics as observed in humans: shortness of breath, lung edema, alveolar septal rupture, infiltration of inflammatory cells, oxidative and inflammatory injury. This suggests that it is feasible to establish animal models using this chamber for the investigation of gas toxicity.

TRIM72 is required for effective repair of alveolar epithelial cell wounding.

The molecular mechanisms for lung cell repair are largely unknown. Previous studies identified tripartite motif protein 72 (TRIM72) from striated muscle and linked its function to tissue repair. In this study, we characterized TRIM72 expression in lung tissues and investigated the role of TRIM72 in repair of alveolar epithelial cells. In vivo injury of lung cells was introduced by high tidal volume ventilation, and repair-defective cells were labeled with postinjury administration of propidium iodide. Primary alveolar epithelial cells were isolated and membrane wounding and repair were labeled separately. Our results show that absence of TRIM72 increases susceptibility to deformation-induced lung injury whereas TRIM72 overexpression is protective. In vitro cell wounding assay revealed that TRIM72 protects alveolar epithelial cells through promoting repair rather than increasing resistance to injury. The repair function of TRIM72 in lung cells is further linked to caveolin 1. These data suggest an essential role for TRIM72 in repair of alveolar epithelial cells under plasma membrane stress failure.

Micromechanics of alveolar edema.

The decrease of lung compliance in pulmonary edema underlies ventilator-induced lung injury. However, the cause of the decrease in compliance is unknown. We tested the hypothesis that in pulmonary edema, the mechanical effects of liquid-filled alveoli increase tissue stress in adjacent air-filled alveoli. By micropuncture of isolated, perfused rat lungs, we established a single-alveolus model of pulmonary edema that we imaged using confocal microscopy. In this model, we viewed a liquid-filled alveolus together with its air-filled neighbor at different transpulmonary pressures, both before and after liquid-filling. Instilling liquid in an alveolus caused alveolar shrinkage. As a result, the interalveolar septum was stretched, causing the neighboring air-filled alveolus to bulge. Thus, the air-filled alveolus was overexpanded by virtue of its adjacency to a liquid-filled alveolus. Confocal microscopy at different depths of the liquid-filled alveolus revealed a meniscus. Lung inflation to near-total lung capacity (TLC) demonstrated decreased compliance of the air-filled but not liquid-filled alveolus. However, at near TLC, the air-filled alveolus was larger than it was in the pre-edematous control tissue. In pulmonary edema, liquid-filled alveoli induce mechanical stress on air-filled alveoli, reducing the compliance of air-filled alveoli, and hence overall lung compliance. Because of increased mechanical stress, air-filled alveoli may be susceptible to overdistension injury during mechanical ventilation of the edematous lung.

ACE2 Promotes the Synthesis of Pulmonary Surfactant to Improve AT II Cell Injury via SIRT1/eNOS Pathway.

OBJECTIVE: We aimed to explore the level of PS, cell viability, inflammatory factors, and apoptosis in neonatal respiratory distress syndrome (ARDS). Besides, we explored the potential relationship between ACE2, SIRT1/eNOS pathway, and hypoxia-induced AT II cell damage. METHODS: The hUC-MSC-derived AT II cells were verified by IF and ICC, whereas qRT-PCR was used for PS and AT II cell marker (CK-8 and KGF). The AT II cell damage model was established by hypoxia exposure. The enhanced expression of ACE2 was tested after transfection with pcDNA3.1-ACE2 by western blot. The effects of hypoxia and ACE2 on AT II cells were evaluated by MTT, western blot, ELISA, and flow cytometry. The involvement of the SIRT1/eNOS pathway in AT II cell's protective functions against NRDS was verified with the addition of SIRT1 inhibitor EX527. RESULTS: Based on the successful differentiation of AT II cells from hUC-MSCs and the buildup of AT II cell damage model, the overexpressed ACE2 impeded the hypoxia-induced cellular damage of AT II cells. It also counteracted the inhibitory effects of hypoxia on the secretion of PS. Overexpression of ACE2 rescued the cell viability and suppressed the secretion of inflammatory cytokines and the apoptosis of AT II cells triggered by hypoxia. And ACE2 activated the SIRT1/eNOS pathway to play its cell-protective and anti-inflammatory roles. CONCLUSION: Our findings provided information that ACE2 prevented AT II cells from inflammatory damage through activating the SIRT1/eNOS pathway, which suggested that ACE2 might become a novel protective agent applied in the protection and treatment of NRDS.

Baicalin attenuates LPS-induced alveolar type II epithelial cell A549 injury by attenuation of the FSTL1 signaling pathway via increasing miR-200b-3p expression.

In China, baicalin is the main active component of Scutellaria baicalensis, which has been used in the treatment of inflammation-related diseases, such as inflammation-induced acute lung injury. However, its specific mechanism remains unclear. This study examined the protective effect of baicalin on LPS-induced inflammation injury of alveolar epithelial cell line A549 and explored its protective mechanism. Compared with the LPS-induced group, the proliferation inhibition rates of alveolar type II epithelial cell line A549 intervened by different concentrations of baicalin decreased significantly, as did the levels of inflammatory factors IL-6, IL-1ß, prostaglandin 2 and TNF-α in the supernatant. The expression levels of inflammatory proteins inducible NO synthase (iNOS), NF-κB65, phosphorylated ERK (p-ERK1/2), and phosphorylated c-Jun N-terminal kinase (p-JNK1) significantly decreased, as did the protein expression of follistatin-like protein 1 (FSTL1). In contrast, expression of miR-200b-3p significantly increased in a dose-dependent manner. These results suggested that baicalin could significantly inhibit the expression of inflammation-related proteins and improve LPS-induced inflammatory injury in alveolar type II epithelial cells. The mechanism may be related to the inhibition of ERK/JNK inflammatory pathway activation by increasing the expression of miR-200b-3p. Thus, FSTL1 is the regulatory target of miR-200b-3p.

Recruitment maneuver in experimental acute lung injury: the role of alveolar collapse and edema.

OBJECTIVE: In acute lung injury, recruitment maneuvers have been used to open collapsed lungs and set positive end-expiratory pressure, but their effectiveness may depend on the degree of lung injury. This study uses a single experimental model with different degrees of lung injury and tests the hypothesis that recruitment maneuvers may have beneficial or deleterious effects depending on the severity of acute lung injury. We speculated that recruitment maneuvers may worsen lung mechanical stress in the presence of alveolar edema. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Thirty-six Wistar rats randomly divided into three groups (n = 12 per group). INTERVENTIONS: In the control group, saline was intraperitoneally injected, whereas moderate and severe acute lung injury animals received paraquat intraperitoneally (20 mg/kg [moderate acute lung injury] and 25 mg/kg [severe acute lung injury]). After 24 hrs, animals were further randomized into subgroups (n = 6/each) to be recruited (recruitment maneuvers: 40 cm H2O continuous positive airway pressure for 40 secs) or not, followed by 1 hr of protective mechanical ventilation (tidal volume, 6 mL/kg; positive end-expiratory pressure, 5 cm H2O). MEASUREMENTS AND MAIN RESULTS: Only severe acute lung injury caused alveolar edema. The amounts of alveolar collapse were similar in the acute lung injury groups. Static lung elastance, viscoelastic pressure, hyperinflation, lung, liver, and kidney cell apoptosis, and type 3 procollagen and interleukin-6 mRNA expressions in lung tissue were more elevated in severe acute lung injury than in moderate acute lung injury. After recruitment maneuvers, static lung elastance, viscoelastic pressure, and alveolar collapse were lower in moderate acute lung injury than in severe acute lung injury. Recruitment maneuvers reduced interleukin-6 expression with a minor detachment of the alveolar capillary membrane in moderate acute lung injury. In severe acute lung injury, recruitment maneuvers were associated with hyperinflation, increased apoptosis of lung and kidney, expression of type 3 procollagen, and worsened alveolar capillary injury. CONCLUSIONS: In the presence of alveolar edema, regional mechanical heterogeneities, and hyperinflation, recruitment maneuvers promoted a modest but consistent increase in inflammatory and fibrogenic response, which may have worsened lung function and potentiated alveolar and renal epithelial injury.

Effects of surfactant replacement on alveolar overdistension and plasma cytokines in ventilator-induced lung injury.

BACKGROUND: Overdistension of the lung causes ventilator-induced lung injury (VILI) accompanied by surfactant abnormalities and inflammatory changes. We investigated the effects of surfactant replacement on overdistension of the terminal airspaces and plasma cytokine levels in VILI. METHODS: VILI was induced by high-pressure ventilation (HPV) in rats anesthetized with pentobarbital, followed by ventilation for 2 h in the maintenance mode (tidal volume=10 ml/kg, positive end-expiratory pressure = 7.5 cmH(2)O) with or without surfactant replacement. The sizes of the terminal airspaces were determined after fixing the lungs at an airway pressure of 10 cmH(2)O on deflation. Cytokine levels were assessed by enzyme-linked immunosorbent assay. RESULTS: The mean ratio of the largest terminal airspace size class (> or = 64,000 microm(2)) was increased from 13.4% to 32.0% by HPV (P<0.05). After maintenance-mode ventilation, the ratio decreased to 16.1% with surfactant replacement (P<0.05), but increased to 44.6% without surfactant replacement (P<0.05). Mean macrophage inflammatory protein-2 (MIP-2) levels in the plasma increased from <0.02 to 6.9 ng/ml with HPV (P<0.05), and further increased to > or = 11.8 ng/ml, regardless of surfactant replacement after maintenance-mode ventilation. Similar tendencies were observed in the interleukin (IL)-6 and IL-10 levels. Tumor necrosis factor-alpha levels were almost negligible during the experiment. CONCLUSION: In rats with VILI, surfactant replacement reversed overdistension of the terminal airspaces that may induce barotrauma, but not upregulation of MIP-2, IL-6, and IL-10 within 2 h.