Cathepsin B and D activity in alveolar macrophages from rats with pulmonary granulomatous inflammation or acute lung injury

Ventilation with a small tidal volume (Vt) is associated with better clinical outcomes than with a large Vt, particularly in critical settings, including acute lung injury. To determine whether Vt influences the lipopolysaccaharide (LPS) recognition pathway, we studied CD14 expression in rabbit lungs and the release of TNF-α by cultured alveolar macrophages after 240 min of ventilation with a large (20 ml/kg) vs. a small (5 ml/kg) Vt. We also applied small or large Vt to lungs instilled with 50 μg/kg of LPS. The alveolar macrophages collected after large Vt ventilation revealed a 20-fold increase in LPS-induced TNF-α release compared with those collected after small Vt ventilation, whereas TNF-α was undetectable without LPS stimulation. In animals ventilated with a large Vt, the expression of CD14 mRNA in whole lung homogenates and the expression of CD14 protein on alveolar macrophages, assessed by immunohistochemistry, were both significantly increased in the absence of LPS stimulation. A large Vt applied to LPS-instilled lungs increased the pulmonary albumin permeability and TNF-α release into the plasma. These results suggest that mechanical stress caused by a large Vt sensitizes the lungs to endotoxin, a phenomenon that may occur partially via the upregulation of CD14.

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Successful Treatment of Acute Lung Injury with Pitavastatin in Septic Mice: Potential Role of Glucocorticoid Receptor Expression in Alveolar Macrophages

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.110.171462 ◽

2010 ◽

Vol 336 (2) ◽

pp. 381-390 ◽

Cited By ~ 35

Author(s):

Ken-ichi Takano ◽

Seiji Yamamoto ◽

Kengo Tomita ◽

Michinori Takashina ◽

Hiroki Yokoo ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Glucocorticoid Receptor ◽

Successful Treatment ◽

Alveolar Macrophages ◽

Potential Role ◽

Receptor Expression

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Dysfunction of CFTR in Alveolar Macrophages and Neutrophils Propagates Production of Proinflammatory Cytokines and Exacerbates Acute Lung Injury in Mice

The FASEB Journal ◽

10.1096/fasebj.21.5.a551-c ◽

2007 ◽

Vol 21 (5) ◽

Author(s):

Xiao Su ◽

Jae Woo Lee ◽

Yuanlin Song ◽

Michael A Matthay

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Proinflammatory Cytokines ◽

Alveolar Macrophages

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Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00422.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. L930-L939 ◽

Cited By ~ 23

Author(s):

Songen Zhang ◽

Milladur Rahman ◽

Su Zhang ◽

Zhongquan Qi ◽

Heiko Herwald ◽

...

Keyword(s):

Gene Expression ◽

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophages ◽

Tissue Injury ◽

Neutrophil Infiltration ◽

Streptococcal Toxic Shock Syndrome ◽

Edema Formation ◽

M1 Protein ◽

Cxcr2 Antagonist

Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung injury. Statins exert beneficial effects in septic patients although the mechanisms remain elusive. This study examined effects of simvastatin on M1 protein-provoked pulmonary inflammation and tissue injury. Male C57BL/6 mice were pretreated with simvastatin or a CXCR2 antagonist before M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for determination of neutrophil infiltration, formation of edema, and CXC chemokines. Flow cytometry was used to determine Mac-1 expression on neutrophils. Gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative RT-PCR. M1 protein challenge caused massive infiltration of neutrophils, edema formation, and production of CXC chemokines in the lung as well as upregulation of Mac-1 on circulating neutrophils. Simvastatin reduced M1 protein-induced infiltration of neutrophils and edema in the lung. In addition, M1 protein-induced Mac-1 expression on neutrophils was abolished by simvastatin. Furthermore, simvastatin markedly decreased pulmonary formation of CXC chemokines and gene expression of CXC chemokines in alveolar macrophages. Moreover, the CXCR2 antagonist reduced M1 protein-induced neutrophil expression of Mac-1 and accumulation of neutrophils as well as edema formation in the lung. These novel findings indicate that simvastatin is a powerful inhibitor of neutrophil infiltration in acute lung damage triggered by streptococcal M1 protein. The inhibitory effect of simvastatin on M1 protein-induced neutrophil recruitment appears related to reduced pulmonary generation of CXC chemokines. Thus, simvastatin may be a useful tool to ameliorate acute lung injury in streptococcal infections.

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Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-dependent Manner

10.21203/rs.3.rs-664786/v1 ◽

2021 ◽

Author(s):

Gaojian Wang ◽

Yaping Zhang ◽

Nianqiang Hu ◽

Qinxue Liu ◽

Fengjie Ma ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophage ◽

Alveolar Macrophages ◽

Macrophage Activation ◽

Rna Seq ◽

Ep4 Receptor ◽

Pge2 Receptor ◽

Cox2 Inhibitor

Abstract Background: Mesenchymal stem cell have shown therapeutic effect on acute lung injury, MSC could be activated when added to inflammatory environment and in turn suppress inflammation, yet the mechanism is complex and not understood. Methods: To determine the effect of MSC on ALI and alveolar macrophage activation, MSCs were administered to ALI mice and co-cultured with activated MH-S cells (alveolar macrophage cell line). To find the genes critical for MSC’s immunosuppressive effects, rest and activated MSCs induced by inflammatory MH-S cells were harvested for RNA-seq. To prove that PGE2 participates in the immunosuppressive effects of MSC, COX2 inhibitor and PGE2 receptor antagonist were added to the co-culture system and administrated to ALI mice. Results: The intratracheal administration of MSCs attenuated ALI and suppressed alveolar macrophages activation in vivo, the activation of MH-S cells was also significantly reduced after co-culturing with MSCs in vitro. The RNA-seq data of rest and activated MSCs suggested that the Ptgs2 gene may play an important role in MSC exerting immunosuppressive effects. Correspondingly, we found that the COX2 protein and PGE2 released by activated MSCs were increased dramatically after co-culturing with MH-S. The use of COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppressive effect on macrophages activation of MSCs in vitro. Furthermore, GW627368X, a selective antagonist of PGE2 receptor (EP4 receptor), also reversed the inhibitory effects of MSCs on alveolar macrophages and their protective effects on ALI mice.Conclusions: MSC attenuate ALI partly through suppressing alveolar macrophage activation via PGE2 binding to EP4 receptor.

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Geranylgeranyl diphosphate synthase deficiency hyperactivates macrophages and aggravates lipopolysaccharide-induced acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00281.2020 ◽

2021 ◽

Author(s):

Jiajia Jin ◽

Hong Qian ◽

Bing Wan ◽

Li Zhou ◽

Cen Chen ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophages ◽

Macrophage Activation ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Alveolar Epithelium ◽

Geranylgeranyl Diphosphate Synthase ◽

Geranylgeranyl Diphosphate

Macrophage activation is a key contributing factor for excessive inflammatory responses of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Geranylgeranyl diphosphate synthase (GGPPS) plays a key role in the development of inflammatory diseases. Our group previously showed that GGPPS in alveolar epithelium have deleterious effects on acute lung injury induced by LPS or mechanical ventilation. Herein, we examined the role of GGPPS in modulating macrophage activation in ALI/ARDS. We found significant increased GGPPS expression in alveolar macrophages in ARDS patients compared to healthy volunteers and in ALI mice induced by LPS. GGPPS-floxed control (GGPPSfl/fl) and myeloid-selective knockout (GGPPSfl/flLysMcre) mice were then generated. Interestingly, using a LPS-induced ALI mouse model, we showed that myeloid-specific GGPPS knockout significantly increased mortality, aggravated lung injury, and increased the accumulation of inflammatory cells, total protein, and inflammatory cytokines in BALF. In vitro, GGPPS deficiency up-regulated the production of LPS-induced IL-6, IL-1β, and TNF-α in alveolar macrophages, bone marrow-derived macrophages (BMDMs), and THP-1 cells. Mechanistically, GGPPS knockout increased phosphorylation and nuclear translocation of NF-κB p65 induced by LPS. In addition, GGPPS deficiency increased the level of GTP-Rac1, which was responsible for NF-κB activation. In conclusion, decreased expression of GGPPS in macrophages aggravates lung injury and inflammation in ARDS, at least partly by regulating Rac1-dependent NF-κB signaling. GGPPS in macrophages may represent a novel therapeutic target in ARDS.

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