Acute Lung Injury Induced by Lipopolysaccharide Is Independent of Complement Activation

Rittirsch, Daniel; Flierl, Michael A.; Day, Danielle E.; Nadeau, Brian A.; McGuire, Stephanie; Hoesel, Laszlo M.; Ipaktchi, Kyros; Zetoune, Firas S.; Sarma, J. Vidya; Leng, Lin; Huber‐Lang, Markus; Neff, Thomas; Bucala, Richard; Ward, Peter A.

doi:10.4049/jimmunol.180.11.7664

Cited by 130 publications

(108 citation statements)

References 51 publications

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“…Evidence is further provided that C5L2, the second receptor for C5a, plays an important antiinflammatory role through inhibition of C5aR signaling, because its deficiency leads to increases in all parameters of inflammation, as well as to changes in lung function. This work therefore underscores the importance of complement activation in LPS-induced lung injury, a concept that has been questioned in recent literature (13). We also corroborate our previous finding of the role of C5L2 in negatively modulating C5a-C5aR activities in models of contact dermatitis and immune complex lung injury (18,19).…”

Section: Discussionsupporting

confidence: 80%

“…Patients with ARDS also show evidence of complement activation, and the degree of activation correlates with the severity of disease, as well as with clinical outcome (7,38,39). Rittirsch and colleagues (13), however, found no detectable C5a in murine BAL fluids after intratracheal LPS administration, and showed that injury was fully expressed in C5 2/2 mice or animals given anti-C5a antibody. The same group later demonstrated that mice deficient in either C5aR or C5L2 are protected from intratracheal LPS (14).…”

Section: Discussionmentioning

confidence: 99%

“…Although it is unquestioned that LPS administration results in complement activation (12), one study suggested that it does not contribute to the pathophysiology associated with ALI/ARDS, because neither antibody blockade of the C5a receptor nor absence of C5 altered the degree of lung damage in this model (13). The same group later showed that ALI induced by either LPS or IgG-immune complexes requires the presence of the C5a-C5a receptor (C5aR) (14), corroborating our initial findings (9).…”

mentioning

confidence: 99%

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C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury

Wang

Liu

Gérard

et al. 2016

Am J Respir Cell Mol Biol

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LPS-induced lung injury in the mouse is one of the most robust experimental models used for studies of acute lung injury (ALI) and acute respiratory distress syndrome in humans. Prior clinical and experimental studies support an important role for complement activation, particularly production of C5a, in the pathophysiology of human ALI/acute respiratory distress syndrome. In the mouse model, however, the precise role of C5a and its receptors is unclear. C5L2, an enigmatic second receptor for C5a, has been characterized, and results have generated substantial debate regarding its in vivo function. Our previous work with human neutrophils revealed a unique role for C5L2 in negatively modulating C5a-C5a receptor (C5aR)-mediated cellular activation, in which antibody-mediated blockade of C5L2 resulted in augmented C5a-C5aR responses. Here, we demonstrate that C5L2 2/2 mice (BALB/c background) administered intranasal LPS exhibit significantly more airway edema and hemorrhage than do wild-type animals. Bronchoalveolar lavage fluid and lung homogenates have significantly more neutrophils and myeloperoxidase activity, as well as proinflammatory cytokines and chemokines. When a blocking antibody against the C5aR was administered before LPS administration, the increased neutrophilic infiltration and cytokine levels were reversed. Thus, our data show not only that C5a contributes significantly to LPS-induced ALI in the mouse, but also that C5L2 plays an important antiinflammatory role in this model through actions resulting at least in part from negative modulation of C5a receptor activation.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury

Wang

Liu

Gérard

et al. 2016

Am J Respir Cell Mol Biol

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“…Increased activity of MPO is a strong indicator of neutrophil migration into the pulmonary parenchyma and the alveolar cavities (Reumaux et al;. MPO concentration has been used for estimation of LPSinduced ALI in many studies, for example, Rittirsch et al (2008), Tsai et al (2014). In the rhamnazin pretreated rats, a marked reduction in the activity of MPO was observed.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and Anti-Inflammatory Effects of Rhamnazin on Lipopolysaccharide-Induced Acute Lung Injury and Inflammation in Rats

Xiao-ping

et al. 2017

Afr J Tradit Complement Altern Med

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Background: Acute Lung Injury (ALI) results into severe inflammation and oxidative stress to the pulmonary tissue. Rhamnazin is a natural flavonoid and known for its antioxidant and anti-inflammatory properties. Materials and methods:The antioxidative and anti-inflammatory properties rhamnazin were tested for protection against the acute lung injury. We investigated whether rhamnazin improves the lipopolysaccharide (LPS)-induced ALI in an animal model (rat). We also studied the probable molecular mechanism of action of rhamnazin. Rhamnazin was injected intraperitoneally (i.p.) (5, 10 and 20 mg/kg) two days before intratracheal LPS challenge (5mg/kg). The changes in lung wet-to-dry weight ratio, LDH activity, pulmonary histopathology, BALF protein concentration, MPO activity, oxidative stress, cytokine production were estimated. Results:The results showed a significant attenuation of all the inflammatory parameters and a marked improvement in the pulmonary histopathology in the animal groups pretreated with rhamnazin. The rhamnazin pretreated group also showed activation of Nrf2 pathway and attenuation of ROS such as H2O2, MDA and hydroxyl ion. These results indicated that rhamnazin could attenuate the symptoms of ALI in rats due to its strong antioxidant and anti-inflammatory properties. Conclusion:The results strongly demonstrated that rhamnazin provides protection against LPS-induced ALI. The underlying mechanisms of its anti-inflammatory action may include inhibition of Nrf2 mediated antioxidative pathway.

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“…The induction of lung injury using intra-tracheal administration of lipopolysaccharide (LPS) has represented a useful model for studying ALI, as it avoids multi-organ failure (7). LPS is a prototypical endotoxin that is a key component of the outer membrane of gram-negative bacteria, including Pseudomonas aeruginosa.…”

Section: Introductionmentioning

confidence: 99%

Biphasic modulation of α-ENaC expression by lipopolysaccharide in vitro and in vivo

Sheng

Nie

et al. 2014

Molecular Medicine Reports

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Abstract. Acute lung injury (ALI) is characterized by pulmonary edema, in which the epithelial sodium channel (ENaC) has a critical role in the clearance of edema fluid from the alveolar space. Lipopolysaccharide (LPS), frequently employed to induce ALI in experimental animal models, has been reported to regulate ENaC expression and alveolar fluid clearance. The role of LPS in regulating ENaC expression is currently controversial, with increases and decreases reported in ENaC expression in response to LPS treatment, as well as reports that ENaC expression is not affected by LPS induction. The present study aimed to systematically analyze the regulation of α-ENaC expression in LPS models of ALI at different pathological stages in vitro and in vivo. ENaC expression was observed to increase ≤8 h after LPS treatment, and to decrease thereafter. This finding may explain the contradictory data regarding α-ENaC expression in response to LPS in the lung. The results of the present study, in combination with those of previous studies, indicate that the modulation of α-ENaC expression may not be a direct genetic response to LPS exposure, but a general response of the lung to the pathological changes associated with inflammation, hypoxia and endothelial and epithelial damage involved in the development of ALI. The findings of this study may have potential clinical significance for understanding the pathogenesis of ALI and improving patient outcome. IntroductionAcute lung injury (ALI) is a clinical syndrome characterized by pulmonary edema and associated with a high mortality rate (1).The pathogenesis of ALI is poorly understood; however, clinical studies have demonstrated that the regulation of epithelial sodium channel (ENaC)-mediated alveolar fluid clearance may represent an effective treatment strategy to improve the outcome for patients with ALI (2,3). ENaC is composed of three homologous subunits, α, β and γ (4). The α subunit is essential for the functional transport of Na + and H 2 O out of the airway lumen. The physiological importance of α-ENaC in the lung has been demonstrated in a study of α-ENaC-knockout mice, where respiratory distress and mortality were observed ≤40 h after birth, as a consequence of an inability to clear fluid from the lungs (5). Furthermore, experimental evidence has indicated that a reduction in α-ENaC expression may impair the resolution of pulmonary edema in patients with ALI (6).To investigate the molecular mechanisms associated with ALI, a variety of experimental models have been used. The induction of lung injury using intra-tracheal administration of lipopolysaccharide (LPS) has represented a useful model for studying ALI, as it avoids multi-organ failure (7). LPS is a prototypical endotoxin that is a key component of the outer membrane of gram-negative bacteria, including Pseudomonas aeruginosa. LPS has been demonstrated to modify Na + transport in the airway epithelium by regulating either ENaC mRNA expression (8) or the ENaC channel current (9). The effect of LPS on α-ENaC express...

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Acute Lung Injury Induced by Lipopolysaccharide Is Independent of Complement Activation

Cited by 130 publications

References 51 publications

C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury

C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury

Antioxidant and Anti-Inflammatory Effects of Rhamnazin on Lipopolysaccharide-Induced Acute Lung Injury and Inflammation in Rats

Biphasic modulation of α-ENaC expression by lipopolysaccharide in vitro and in vivo

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