Increase In Pulmonary Vascular Permeability Research Articles

Schisandrin A ameliorates increased pulmonary capillary endothelial permeability accompanied with sepsis through inhibition of RhoA/ROCK1/MLC pathways.

Sepsis is a systemic inflammatory response, and vascular leakage associated with acute lung injury (ALI) is an important pathophysiological process during sepsis. Schisandrin A (SchA) is a bioactive lignan which has been reported to have the anti-inflammatory effects in many studies, while whether SchA can ameliorate ALI-related vascular leakage caused by sepsis is unknown. To evaluate the role and the underlying mechanism of SchA in increase of pulmonary vascular permeability induced by sepsis. The effect of SchA on pulmonary vascular permeability was examined in rat acute lung injury model. The effect of SchA on skin vascular permeability of mice was investigated through Miles assay. MTT assay was performed to detect the cell activity, and transwell assay was used to detect the effect of SchA on cell permeability. The effects of SchA on junction proteins and RhoA/ROCK1/MLC signaling pathway were manifested by immunofluorescence staining and western blot. The administration of SchA alleviated rat pulmonary endothelial dysfunction, relieved increased permeability in the mouse skin and HUVECs induced by lipopolysaccharide (LPS). Meanwhile, SchA inhibited the formation of stress fibers, reversed the decrease of expression of ZO-1 and VE-cadherin. Subsequent experiments confirmed that SchA inhibited RhoA/ROCK1/MLC canonical pathway in rat lungs and HUVECs induced by LPS. Moreover, overexpression of RhoA reversed the inhibitory effect of SchA in HUVECs, which suggested that SchA protected the pulmonary endothelial barrier by inhibiting RhoA/ROCK1/MLC pathway. In summary, our results indicate that SchA ameliorates the increase of pulmonary endothelial permeability induced by sepsis through inhibition of RhoA/ROCK1/MLC pathway, providing a potentially effective therapeutic strategy for sepsis.

Relationship of Extravascular Lung Water and Pulmonary Vascular Permeability to Respiratory Mechanics in Patients with COVID-19-Induced ARDS

During acute respiratory distress syndrome (ARDS), the increase in pulmonary vascular permeability and lung water induced by pulmonary inflammation may be related to altered lung compliance. A better understanding of the interactions between respiratory mechanics variables and lung water or capillary permeability would allow a more personalized monitoring and adaptation of therapies for patients with ARDS. Therefore, our main objective was to investigate the relationship between extravascular lung water (EVLW) and/or pulmonary vascular permeability index (PVPI) and respiratory mechanic variables in patients with COVID-19-induced ARDS. This is a retrospective observational study from prospectively collected data in a cohort of 107 critically ill patients with COVID-19-induced ARDS from March 2020 to May 2021. We analyzed relationships between variables using repeated measurements correlations. We found no clinically relevant correlations between EVLW and the respiratory mechanics variables (driving pressure (correlation coefficient [CI 95%]: 0.017 [-0.064; 0.098]), plateau pressure (0.123 [0.043; 0.202]), respiratory system compliance (-0.003 [-0.084; 0.079]) or positive end-expiratory pressure (0.203 [0.126; 0.278])). Similarly, there were no relevant correlations between PVPI and these same respiratory mechanics variables (0.051 [-0.131; 0.035], 0.059 [-0.022; 0.140], 0.072 [-0.090; 0.153] and 0.22 [0.141; 0.293], respectively). In a cohort of patients with COVID-19-induced ARDS, EVLW and PVPI values are independent from respiratory system compliance and driving pressure. Optimal monitoring of these patients should combine both respiratory and TPTD variables.

Propofol Affects H/R Induced Alveolar Macrophage Death via TLR4/NF-κB/NLRP3 Signaling Pathway

Acute lung injury (ALI) is one of the most common acute and critical diseases in clinic. The main pathological features of ALI are increase of pulmonary Vascular permeability, accumulation of inflammatory cells and pulmonary dysfunction due to diffuse pulmonary edema. At present, it is generally believed that the main pathogenesis of ALI is the uncontrolled inflammatory response in the lung. It has been found that cell death plays an important role in the regulation of inflammatory reaction in acute lung injury. Propofol, a new fast-acting, short-acting intravenous anesthetic, it is known that ALI can be alleviated by inhibiting the release of inflammatory factors and inhibiting the anoxia/reoxygenation-induced autophagy, chemotaxis and oxidative stress in macrophages, however, the mechanism of its role in the death of alveolar macrophage remains unknown. Therefore, the aim of this study was to investigate the role of propofol in alveolar macrophage death and its mechanism through anoxia-reoxygenation induced ALI. NR8383 was alveolar macrophage as anoxia-reoxygenation model. LDH release, CCK-8, Elisa and Western Blot were used to investigate the pathway of propofol through TLR4/NF-κB/NLRP3 signaling pathway, mechanism of inhibition of hypoxia-reoxygenation induced alveolar macrophage death of NR8383. The results showed that propofol decreased the release of LDH and the content of IL-1β and IL-18. In addition, propofol pretreatment reduced the protein expression levels of TLR4 downstream pathways (p65 phosphorylation, NLRP3, cleaved-caspase-1, and GSDMD-N), all of which could be reversed by TLR4 receptor antagonist and NLRP3 receptor inhibitors, it’s causing a decrease in alveolar macrophage activity. The results showed that propofol could significantly reduce anoxia-reoxygenation-induced alveolar macrophage death. Propofol may modulate alveolar macrophage death through TLR4/NF-κB/NLRP3 inflammatory signaling pathway, thereby alleviating anoxia-reoxygenation induced Ali, suggesting that propofol may be a potential drug for the treatment of Ali.

Agonists for Bitter Taste Receptors T2R10 and T2R38 Attenuate LPS-Induced Permeability of the Pulmonary Endothelium in vitro.

One of the hallmarks of acute respiratory distress syndrome (ARDS) is an excessive increase in pulmonary vascular permeability. In settings of ARDS, the loss of barrier integrity is mediated by cell–cell contact disassembly and actin remodelling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability seen in ARDS. Bitter taste receptors (T2Rs) belong to the superfamily of G-protein-coupled receptors found in several extraoral systems, including lung epithelial and smooth muscle cells. In the present study, we show for the first time that several T2Rs are expressed in human pulmonary arterial endothelial cells (HPAECs). Our results focus on those which are highly expressed as: T2R10, T2R14 and T2R38. Agonists for T2R10 (denatonium) and T2R38 (phenylthiourea), but not T2R14 (noscapine), significantly attenuated lipopolysaccharide (LPS)-induced permeability and VE-cadherin internalisation in HPAECs. In T2R10- or T2R38-siRNA knockdown cells, these endothelial-protective effects were abolished, indicating a direct effect of agonists in regulating barrier integrity. Our further findings indicate that T2R10 and T2R38 exert their barrier-protective function through cAMP but via Rac1-dependent and independent pathways, respectively. However, using an in vivo model of ARDS, the T2R38 agonist, phenylthiourea, was not able to protect against pulmonary edema formation. Taken together, these studies identify bitter taste sensing in the pulmonary endothelium to regulate barrier integrity in vitro through cAMP-Rac1 signalling.

The effects of human prothrombin complex concentrate on hemorrhagic shock-induced lung injury in rats: Implications for testing human blood products in rodents.

Hemorrhagic shock (HS) and trauma can result in an endotheliopathy of trauma, characterized by endothelial compromise, inflammation, and aberrant coagulation. Kcentra, a prothrombin concentrate, has been demonstrated to mitigate pulmonary vascular leak in a murine model of HS. We investigated the effects of Kcentra in a rat model of HS, to achieve physiologic endpoints of relevance. Rats subjected to a grade intravenous splenic injury and controlled hemorrhage for 60 minutes were resuscitated with shed volumes of (1) Lactated Ringer's (LR) solution, (2) LR + 20 IU/kg Kcentra, (3) LR + 50 IU/kg Kcentra, (4) rat fresh frozen plasma (RFFP), or (5) human fresh frozen plasma (HFFP). Blood was harvested for monitoring metabolic and coagulation function. Rat lungs were evaluated for lung injury and permeability. Animals resuscitated with LR displayed a significant increase in pulmonary vascular permeability (sham, 407.9 ± 122.4; shock + LR, 2040 ± 1462). Resuscitation with RFFP (606.5 ± 169.3) reduced leak; however, treatment with Kcentra (HS + Kcentra [20 IU/kg]: 1792 ± 903.4, HS + Kcentra [50 IU/kg]: 1876 ± 1103), and HFFP (1450 ± 533.2) had no significant effect on permeability. Kcentra modestly altered clotting parameters. Metabolic measures, such as lactate, pH, and base deficit, were restored to baseline levels by both RFFP and HFFP, but not Kcentra or LR. Kcentra did not alter pulmonary vascular permeability, but modestly increased clotting potential in injured rats. This suggests that there may be a xenogenic reaction of human products in rats and that the effects of Kcentra on vascular stability may be distinct from its ability to modulate clotting. Our data indicate that the species chosen and utilized for in vivo preclinical testing of human derived blood products is of critical importance in determining their efficacy in animal models and is the primary impetus to communicate these results.

Fraxin Alleviates LPS-Induced ARDS by Downregulating Inflammatory Responses and Oxidative Damages and Reducing Pulmonary Vascular Permeability

Acute respiratory distress syndrome (ARDS) is a severe acute disease that threatens human health, and few drugs that can effectively treat this disease are available. Fraxin, one of the main active ingredients of Cortex Fraxini, a Chinese herbal medicine, has presented various pharmacological and biological activities. However, the effects of fraxin on ARDS have yet to be reported. In the present study, the protective effect of fraxin in lipopolysaccharide (LPS)-induced ARDS in a mouse model was analyzed. Results from the hematoxylin and eosin staining showed that fraxin might alleviate pathological changes in the lung tissues of mice with ARDS. ELISA and Western blot results revealed that fraxin might inhibit the production of inflammatory factors, namely, IL-6, TNF-α, and IL-1β, and the activation of NF-κB and MAPK signaling pathways in the lungs. Thus, the inflammatory responses were reduced. Fraxin might inhibit the increase in reactive oxygen species (ROS) and malondialdehyde (MDA), a product of lipid peroxidation in lung tissues. Fraxin might increase the superoxide dismutase (SOD) activity to avoid oxidative damage. Vascular permeability was also assessed through Evans blue dye tissue extravasation and fluorescein isothiocyanate-labeled albumin (FITC-albumin) leakage. Fraxin might inhibit the increase in pulmonary vascular permeability and relieve pulmonary edema. Fraxin was also related to the inhibition of the increase in matrix metalloproteinase-9, which is a glycocalyx-degrading enzyme, and the relief of damages to the endothelial glycocalyx. Thus, fraxin elicited protective effects on mice with LPS-induced ARDS and might be used as a drug to cure ARDS induced by Gram-negative bacterial infection.

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice.

Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide‐induced ALI was used to investigate the migration of AT2R‐regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II‐enhanced human bone marrow MSC migration in vitro. Moreover, MSC‐AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC‐AT2R‐injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti‐inflammatory effects. In contrast, there were less lung retention in MSC‐ShAT2R‐injected ALI mice compared with MSC‐Shcontrol after transplantation. Thus, MSC‐ShAT2R‐injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine 2018;7:721–730

Intercomunicación pulmón-riñón en el paciente crítico

Despite advances in the development of renal replacement therapy, mortality of acute renal failure remains high, especially when occurring simultaneously with distant organic failure as it is in the case of the acute respiratory distress syndrome. In this update, birideccional deleterious relationship between lung and kidney on the setting of organ dysfunction is reviewed, which presents important clinical aspects of knowing. Specifically, the renal effects of acute respiratory distress syndrome and the use of positive-pressure mechanical ventilation are discussed, being ventilator induced lung injury one of the most common models for studying the lung-kidney crosstalk. The role of renal failure induced by mechanical ventilation (ventilator-induced kidney injury) in the pathogenesis of acute renal failure is emphasized. We also analyze the impact of the acute renal failure in the lung, recognizing an increase in pulmonary vascular permeability, inflammation, and alteration of sodium and water channels in the alveolar epithelial. This conceptual model can be the basis for the development of new therapeutic strategies to use in patients with multiple organ dysfunction syndrome.

Global end-diastolic volume is an important contributor to increased extravascular lung water in patients with acute lung injury and acuterespiratory distress syndrome: a multicenter observational study.

BackgroundExtravascular lung water (EVLW), as measured by the thermodilution method, reflects the extent of pulmonary edema. Currently, there are no clinically effective treatments for preventing increases in pulmonary vascular permeability, a hallmark of lung pathophysiology, in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this study, we examined the contributions of hemodynamic and osmolarity factors, for which appropriate interventions are expected in critical care, to EVLW in patients with ALI/ARDS.MethodsWe performed a subgroup analysis of a multicenter observational study of patients with acute pulmonary edema. Overall, 207 patients with ALI/ARDS were enrolled in the study. Multivariate regression analysis was used to evaluate the associations of hemodynamic and serum osmolarity parameters with the EVLW index (EVLWI; calculated as EVLW/Ideal body weight). We analyzed factors measured on the day of enrollment (day 0), and on days 1 and 2 after enrollment.ResultsMultivariate regression analysis showed that global end-diastolic volume index (GEDVI) was significantly associated with EVLWI measured on days 0, 1, and 2 (P = 0.002, P < 0.001, and P = 0.003, respectively), whereas other factors were not significantly associated with EVLWI measured on all 3 days.ConclusionsAmong several hemodynamic and serum osmolarity factors that could be targets for appropriate intervention, GEDVI appears to be a key contributor to EVLWI in patients with ALI/ARDS.Trial registrationUniversity Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000003627.

Gap junction channel protein connexin40 modulates rabbit pulmonary microvascular endothelial cells permeability in traumatic acute lung injury

Objective To investigate the influence of traumatic acute lung injury (ALI) rabbit serum on gap junction channel ( GJC ) function and connexin40 ( Cx40) expression, and the correlation of GJC and Cx40 with rabbit pulmonary microvascular endothelial cells permeability. Methods Cultured pulmonary microvessel endothelial cells were divided into three groups, control ( Gcontrol) , injured serum (Gserum) , and blocker agent ( Gblocker). GJC function was assessed by scrape-loading and dye transfer techniques. Pulmonary microvessel endothelial cells permeability was measured by Evans blue-labeled albumin transfer, and the expression of Cx40 was measured by Western blotting. Intracellular free calcium concentration was measured by fluo-3am. Results Injured serum decreased GJC function and the level of Cx40,which was aggravated by the GJC blocker (control 726 293. 2 ± 83 684. 1, serum 397 798. 1 ± 87 145. 7, blocker 316 977. 6 ±76 325. 9,n=4,P ＜0. 05). Similarly, pulmonary microvascular endothelial cells permeability was increased significantly in Gserum and Gblocker as compared with Gcontrol (P ＜0. 05). After treatment with injured serum in combination with gap junction blocker in vitro, intracellular free calcium concentration was increased [control (494. 80 ±41.94) nmol/L, serum (569. 80 ±6. 70) nmol/L, blocker (158. 80 ±13. 09) nmol/L, P＜ 0.05]. Conclusion Traumatic ALI rabbit serum inhibits the Cx40 expression and down-regulates GJC function, which contributes to the increase of pulmonary microvascular endothelial cells permeability after ALI This mechanism may participate in the increase of pulmonary vascular permeability and promote the morbidity of ALI after trauma. Key words: Acute lung injury; Connexin40; Pulmonary permeability

Tetramethylpyrazine Inhibits Hypoxia-Induced Pulmonary Vascular Leakage in Rats via the ROS-HIF-VEGF Pathway

Tetramethylpyrazine (TMP) is a reactive oxygen species (ROS) antagonist that has potent properties for the treatment of a variety of vascular diseases, such as ischemic stroke and pulmonary hypertension secondary to chronic obstructive pulmonary diseases. However, there are few data about the role of TMP in hypoxia-induced pulmonary vascular leakage. This study examined the effect of TMP on hypoxia-induced pulmonary vascular leakage and the underlying mechanisms. Rat pulmonary microvascular endothelial cells (RPMVECs) treated with TMP or not were subjected to hypoxic or normoxic conditions for 24 h, and the monolayer permeability, intracellular ROS, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) proteins levels were determined. Additionally, rats administrated TMP were exposed to hypobaric hypoxia to evaluate the effect of TMP in vivo by measuring lung water content, pulmonary vascular leakage into the lungs and immunohistochemistry for HIF-1α and VEGF. Hypoxia was found to cause a significant increase in RPMVEC monolayer permeability and intracellular ROS, HIF-1α and VEGF protein levels. Treatment with TMP decreased the hypoxia-induced RPMVEC monolayer permeability and attenuated the elevation of ROS, HIF-1α and VEGF protein levels. TMP-treated animals showed less pulmonary vascular leakage and HIF-1α and VEGF expression compared with those exposed to hypoxia alone. These observations supported that TMP inhibited the increase in pulmonary vascular permeability induced by hypoxia. The underlying mechanisms may be related to the scavenging of intracellular ROS and the suppression of hypoxia-induced upregulation of HIF-1α and VEGF proteins.

Sulfonated immunoglobulin improves cardiopulmonary functions by promoting IGF-I production in ARDS patients with severe sepsis

It has been emphasized that severe sepsis often leads to shock and ARDS in critically ill patients. We reported previously that sulfonated immunoglobulin (sIG) administration significantly inhibited the increase of in lung MPO activities and the increase of pulmonary vascular permeability. In the present study, we examined whether sIG improves not only ARDS but also cardiovascular dysfunction in patients with severe sepsis.

Increase in pulmonary vascular permeability caused by increased expression of Mac-1 on the surface of polymorphonuclear leukocytes

We studied the expression of adhesion molecules on the surface of human polymorphonuclear leukocytes (PMNs). The effects of mechanical stimulation were measured with a flow cytometer and pulmonary vascular injury due to accumulation of PMNs in the lungs was assessed by a gravimetric method. The accumulation of PMNs in the lungs was studied by measuring the amount of myeloperoxidase. PMNs were stimulated by gentle agitation in a glass container for 10 s. Mac-1 (CD11b/CD18) was upregulated on the surface of PMNs that were mechanically stimulated. When unstimulated PMNs were exposed to isolated rat lungs, the filtration coefficient did not change from that under baseline conditions. However, when mechanically stimulated PMNs were exposed to isolated rat lungs, the filtration coefficient was about 5 times higher than that measured at baseline. When mechanically stimulated PMNs treated with anti-CD18 antibody were used, the increase in the filtration coefficient was completely blocked. The assay of myeloperoxidase revealed that PMNs stuck to isolated rat lungs only after stimulated PMNs were added. We conclude that when the adhesiveness of PMNs is increased by mechanical stimulation, these cells adhere to pulmonary vessels and increase pulmonary vascular permeability.

Role of cyclooxygenase metabolites in the increase in pulmonary vascular permeability caused by mechanically activated white blood cells

To study the role of cyclooxygenase metabolites in changes in the pulmonary vasculature induced by mechanically activated white blood cells (WBCs), the effects of activated and inactive WBCs, and of a cyclooxygenase inhibitor, were studied in isolated perfused lungs from Sprague-Dawley rats. WBCs were activated by gentle agitation in a glass container for 10s. Baseline measurements were made, and then activated or inactive WBCs were added to the perfusate. Perfusion was stopped for 90 minutes, and then started again. The effects of the cyclooxygenase inhibitor meclofenamate on the pulmonary vascular filtration coefficient and on pulmonary vascular resistance were also measured. In the group that received activated WBCs, the pulmonary vascular filtration coefficient and the pulmonary vascular resistance were about 2.5 times and 3.3 times higher, respectively, than those in the group that received inactive WBCs. However, this apparent increase in the filtration coefficient caused by activated WBCs was partly blocked by meclofenamate. Histological examination indicated that meclofenamate did not prevent the adhesion of WBCs to the pulmonary vascular endothelium. These date indicate that WBCs that have been made to adhere to vessel walls can induce pulmonary vascular injury via cyclooxygenase products.

Mitogen Activated Protein Kinase Activated Protein Kinase 2 Regulates Actin Polymerization and Vascular Leak in Ventilator Associated Lung Injury

Mechanical ventilation, a fundamental therapy for acute lung injury, worsens pulmonary vascular permeability by exacting mechanical stress on various components of the respiratory system causing ventilator associated lung injury. We postulated that MK2 activation via p38 MAP kinase induced HSP25 phosphorylation, in response to mechanical stress, leading to actin stress fiber formation and endothelial barrier dysfunction. We sought to determine the role of p38 MAP kinase and its downstream effector MK2 on HSP25 phosphorylation and actin stress fiber formation in ventilator associated lung injury. Wild type and MK2−/− mice received mechanical ventilation with high (20 ml/kg) or low (7 ml/kg) tidal volumes up to 4 hrs, after which lungs were harvested for immunohistochemistry, immunoblotting and lung permeability assays. High tidal volume mechanical ventilation resulted in significant phosphorylation of p38 MAP kinase, MK2, HSP25, actin polymerization, and an increase in pulmonary vascular permeability in wild type mice as compared to spontaneous breathing or low tidal volume mechanical ventilation. However, pretreatment of wild type mice with specific p38 MAP kinase or MK2 inhibitors abrogated HSP25 phosphorylation and actin polymerization, and protected against increased lung permeability. Finally, MK2−/− mice were unable to phosphorylate HSP25 or increase actin polymerization from baseline, and were resistant to increases in lung permeability in response to HVT MV. Our results suggest that p38 MAP kinase and its downstream effector MK2 mediate lung permeability in ventilator associated lung injury by regulating HSP25 phosphorylation and actin cytoskeletal remodeling.

Mobilization and Margination of Bone Marrow Gr-1high Monocytes during Subclinical Endotoxemia Predisposes the Lungs toward Acute Injury

The specialized role of mouse Gr-1(high) monocytes in local inflammatory reactions has been well documented, but the trafficking and responsiveness of this subset during systemic inflammation and their contribution to sepsis-related organ injury has not been investigated. Using flow cytometry, we studied monocyte subset margination to the pulmonary microcirculation during subclinical endotoxemia in mice and investigated whether marginated monocytes contribute to lung injury in response to further septic stimuli. Subclinical low-dose i.v. LPS induced a rapid (within 2 h), large-scale mobilization of bone marrow Gr-1high monocytes and their prolonged margination to the lungs. With secondary LPS challenge, membrane TNF expression on these premarginated monocytes substantially increased, indicating their functional priming in vivo. Zymosan challenge produced small increases in pulmonary vascular permeability, which were markedly enhanced by the preadministration of low-dose LPS. The LPS-zymosan-induced permeability increases were effectively abrogated by pretreatment (30 min before zymosan challenge) with the platelet-activating factor antagonist WEB 2086 in combination with the phosphatidylcholine-phospholipase C inhibitor D609, suggesting the involvement of platelet-activating factor/ceramide-mediated pathways in this model. Depletion of monocytes (at 18 h after clodronate-liposome treatment) significantly attenuated the LPS-zymosan-induced permeability increase. However, restoration of normal LPS-induced Gr-1high monocyte margination to the lungs (at 48 h after clodronate-liposome treatment) resulted in the loss of this protective effect. These results demonstrate that mobilization and margination of Gr-1high monocytes during subclinical endotoxemia primes the lungs toward further septic stimuli and suggest a central role for this monocyte subset in the development of sepsis-related acute lung injury.

Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

A significant role for alveolar macrophages (AM) in the pathophysiology of sepsis-induced acute lung injury (ALI) has been shown; however, the mechanisms behind AM-related lung injury remain relatively uncertain. We examined the role of AM nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in pulmonary endothelial cell septic injury. NADPH oxidase is one of the major sources of cellular reactive oxygen species and has been implicated in endothelial injury in ALI. Pulmonary microvascular endothelial cells (PMVEC) monolayers were grown on Transwell inserts and incubated with wild-type and NADPH oxidase-deficient AM in the presence or absence of cytomix (equimolar TNF-alpha, IL-1beta, and IFN-gamma). Injury to the monolayers was assessed by trans-PMVEC Evans blue (EB)-labeled albumin flux. We found AM under cytomix stimulation caused significant EB-albumin flux across the PMVEC monolayers, and this effect was attenuated by the genetic deletion of AM NADPH oxidase. The pharmacological inhibition of AM NADPH oxidase with apocynin and PR-39 also significantly reduced AM-dependent PMVEC injury. In the AM-PMVEC cocultures, we also assessed PMVEC injury through measurement of protein oxidation and lipid peroxidation. AM were shown to cause a significant increase in these markers of PMVEC injury, which was also attenuated by the inhibition of NADPH oxidase or through the use of NADPH oxidase-deficient AM. PMVEC NADPH oxidase was shown not to significantly contribute to PMVEC injury in our studies. From our findings we have concluded that AM NADPH oxidase is crucial for the septic increase in pulmonary vascular permeability.

Role of platelet activating factor in pathogenesis of acute respiratory distress syndrome

Role of platelet activating factor in pathogenesis of acute respiratory distress syndrome

Distant organ injury following acute kidney injury

(AKI) is associated with unacceptablyhigh mortality that can range from 40 to 60% in some cases(14). The incidence of AKI continues to increase (15, 16) andis associated with a changing spectrum of illnesses, significantcomorbidandextrarenalcomplications(12),andunsatisfactorypreventive or treatment strategies (5). The etiology of AKI isdiverse, and ischemia constitutes the major cause of thiscondition. Ischemic AKI is a dynamic process that oftencoexists with multiple organ failure and involves hemody-namic alteration, inflammation, and direct injury to the tubularepithelium (9). Interestingly, renal failure per se usually is notthe cause of death in AKI (7), but rather both cardiogenic (2,10) and noncardiogenic acute lung injury (ALI) (13) accountfor the high mortality associated with AKI. These comorbidconditions can explain the failed treatment regimens, espe-cially when mortality is used as a clinical trial end point.Currently, the mortality of combined AKI and ALI is ex-tremely high and may approach 80% (11). Therefore, definingthe mechanism by which AKI causes ALI is important if weare to be successful in reducing overall mortality associatedwith AKI. Experimental studies demonstrated increased pul-monary vascular permeability, lung edema, alveolar hemor-rhage, and leukocyte trafficking following ischemic AKI (1, 6,8). The recent work of Hoke et al. (4) has shed new light on therole of the kidney in lung injury. In their study, they sought todetermine the the effect of an acute cessation of kidneyfunctiononlunginjury.Theabsenceofclearancewasachievedby either bilateral nephrectomies or by bilateral renal pedicleclamps. The latter method using bilateral pedicles clamp for 22min was associated with effects related to ischemia-reperfusion.AKI induced by ischemia-reperfusion or bilateral nephrectomywas associated with a change in level and pattern of serumcytokines. However, lung injury was similar following renalischemia-reperfusion or bilateral nephrectomies. These resultssuggest that the absence of kidneys results in lung injuryindependent of ischemia-reperfusion. By inference, these re-sults indicate a potentially important role that the kidneys playin maintaining serum cytokine balance and pulmonary ho-meostasis.In this issue of the

Neutrophil degranulation and increased pulmonary capillary permeability following oesophagectomy: a model of early lung injury in man.

In nine subjects undergoing oesophagectomy a transient but significant increase in pulmonary vascular permeability to transferrin was detected in both lungs 8 h after surgery. It coincided with a significant increase in plasma lactoferrin, evidence of intravascular and intra-alveolar neutrophil elastase release and with arterial hypoxaemia. The postoperative state in these patients had intravascular and pulmonary features often associated with the adult respiratory distress syndrome, and might be a useful model for the study of the early inflammatory events underlying lung injury in man.