Rho signaling inhibition mitigates lung injury via targeting neutrophil recruitment and selectin-AKT signaling

Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-α (TNF-α), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.

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Protective Effects of Isoflurane Pretreatment in Endotoxin-induced Lung Injury

Anesthesiology ◽

10.1097/00000542-200603000-00019 ◽

2006 ◽

Vol 104 (3) ◽

pp. 511-517 ◽

Cited By ~ 84

Author(s):

Jörg Reutershan ◽

Daniel Chang ◽

John K. Hayes ◽

Klaus Ley

Keyword(s):

Lung Injury ◽

Bronchoalveolar Lavage ◽

Neutrophil Migration ◽

Neutrophil Recruitment ◽

Pulmonary Vasculature ◽

Lung Edema ◽

Protective Effects ◽

Protein Leakage ◽

Endotoxin Exposure ◽

Organ Systems

Background The concept of antiinflammatory effects of volatile anesthetics is well established in vitro and in some organ systems. Their protective role in lung injury, however, remains to be elucidated. The authors hypothesized that in the lung, isoflurane pretreatment may attenuate neutrophil infiltration and reduce endotoxin-induced injury. Methods Male C57Bl/6 mice were exposed to aerosolized lipopolysaccharide. Neutrophil recruitment into the pulmonary vasculature and migration into the different lung compartments (interstitium and alveolar air space) were determined by flow cytometry. Capillary protein leakage, formation of lung edema, and concentration of the chemokines keratinocyte-derived chemokine (CXCL1) and macrophage inflammatory protein 2 (CXCL2/3) in bronchoalveolar lavage were compared in mice with or without isoflurane treatment (1.4% inspired for 30 min) at different times before and after endotoxin exposure. Results Endotoxin inhalation induced significant neutrophil migration into all lung compartments. Isoflurane pretreatment attenuated both neutrophil recruitment into lung interstitium and alveolar space when given 1 or 12 h before or 1 h after lipopolysaccharide but not at 4, 6, or 24 h before endotoxin exposure. Isoflurane pretreatment 1 or 12 h before lipopolysaccharide also reduced protein leakage and pulmonary edema. Production of CXCL1 and CXCL2/3 in the bronchoalveolar lavage was reduced when isoflurane was given 1 h but not 12 h before lipopolysaccharide, suggesting different mechanisms for early and late protection. Conclusion Isoflurane pretreatment reduces acute lung injury when given 1 or 12 h before an endotoxin challenge or within the first hour of an already established inflammation.

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Fas-deficient mice have impaired alveolar neutrophil recruitment and decreased expression of anti-KC autoantibody:KC complexes in a model of acute lung injury

Respiratory Research ◽

10.1186/1465-9921-13-91 ◽

2012 ◽

Vol 13 (1) ◽

pp. 91 ◽

Cited By ~ 3

Author(s):

Sucheol Gil ◽

Alex W Farnand ◽

William A Altemeier ◽

Sean E Gill ◽

Anna Kurdowska ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Neutrophil Recruitment ◽

Deficient Mice

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A self‐organized actomyosin drives multiple intercellular junction disruption and directly promotes neutrophil recruitment in lipopolysaccharide‐induced acute lung injury

The FASEB Journal ◽

10.1096/fj.201701506rr ◽

2018 ◽

Vol 32 (11) ◽

pp. 6197-6211 ◽

Cited By ~ 4

Author(s):

Bing Chen ◽

Zhen Yang ◽

Congwen Yang ◽

Wenhan Qin ◽

Jianteng Gu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Neutrophil Recruitment ◽

Intercellular Junction ◽

Self Organized

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Arctiin Prevents LPS-Induced Acute Lung Injury via Inhibition of PI3K/AKT Signaling Pathway in Mice

Inflammation ◽

10.1007/s10753-018-0856-x ◽

2018 ◽

Vol 41 (6) ◽

pp. 2129-2135 ◽

Cited By ~ 9

Author(s):

Bo Zhou ◽

Guohu Weng ◽

Zhengxin Huang ◽

Tao Liu ◽

Feiyue Dai

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Signaling Pathway ◽

Akt Signaling ◽

Akt Signaling Pathway

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“Pioglitazone attenuates endotoxin-induced acute lung injury by reducing neutrophil recruitment.” Jochen Grommes, Mathias Mörgelin and Oliver Soehnlein. Eur Respir J 2012; 40: 416–423

European Respiratory Journal ◽

10.1183/13993003.50910-2011 ◽

2020 ◽

Vol 56 (4) ◽

pp. 1150910

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Neutrophil Recruitment

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Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity

Thorax ◽

10.1136/thoraxjnl-2019-213357 ◽

2020 ◽

Vol 75 (3) ◽

pp. 253-261 ◽

Cited By ~ 6

Author(s):

Inga Wessels ◽

Johanna Theresa Pupke ◽

Klaus-Thilo von Trotha ◽

Alexander Gombert ◽

Anika Himmelsbach ◽

...

Keyword(s):

Lung Injury ◽

Zinc Supplementation ◽

Inflammatory Diseases ◽

Risk Groups ◽

Lavage Fluid ◽

Neutrophil Recruitment ◽

Polymorphonuclear Neutrophils ◽

Lung Damage ◽

Inflammatory Status

IntroductionZinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested.Methods64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well.ResultsInjecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail.ConclusionZinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

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