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1.
Front Immunol ; 12: 687506, 2021.
Article in English | MEDLINE | ID: mdl-34484184

ABSTRACT

Surfactant protein D (SP-D) plays an important role in innate and adaptive immune responses. In this study, we found that the expression of total and de-oligomerized SP-D was significantly elevated in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI). To investigate the role of the lower oligomeric form of SP-D in the pathogenesis of ALI, we treated bone marrow-derived macrophages (BMDMs) with ALI-derived bronchoalveolar lavage (BAL) and found that SP-D in ALI BAL predominantly bound to calreticulin (CALR) on macrophages, subsequently increasing the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and expression of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-10, and CD80. However, anti-SP-D (aSP-D) and anti-calreticulin (aCALR) pretreatment reversed the SP-D binding and activation of macrophages induced by ALI BAL or de-oligomerized recombinant murine SP-D (rSP-D). Lack of signal transducer and activator of transcription (STAT)6 in STAT6-/- macrophages resulted in resistance to suppression by aCALR. Further studies in an ALI mouse model showed that blockade of pulmonary SP-D by intratracheal (i.t.), but not intraperitoneal (i.p.), administration of aSP-D attenuated the severity of ALI, accompanied by lower neutrophil infiltrates and expression of IL-1beta and IL-6. Furthermore, i.t. administration of de-oligomerized rSP-D exacerbated the severity of ALI in association with more pro-inflammatory CD45+Siglec-F(-) M1 subtype macrophages and production of IL-6, TNF-alpha, IL-1beta, and IL-18. The results indicated that SP-D in the lungs of murine ALI was de-oligomerized and participated in the pathogenesis of ALI by predominantly binding to CALR on macrophages and subsequently activating the pro-inflammatory downstream signaling pathway. Targeting de-oligomerized SP-D is a promising therapeutic strategy for the treatment of ALI and acute respiratory distress syndrome (ARDS).


Subject(s)
Acute Lung Injury/enzymology , Calbindin 2/metabolism , Lung/enzymology , Macrophage Activation , Macrophages/enzymology , Pulmonary Surfactant-Associated Protein D/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/immunology , Animals , Antibodies/pharmacology , Calbindin 2/antagonists & inhibitors , Cytokines/metabolism , Disease Models, Animal , Inflammation Mediators/metabolism , Lipopolysaccharides , Lung/drug effects , Lung/immunology , Lung/pathology , Macrophage Activation/drug effects , Macrophages/drug effects , Macrophages/immunology , Macrophages/pathology , Male , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Neutrophil Infiltration , Phenotype , Phosphorylation , Pulmonary Surfactant-Associated Protein D/antagonists & inhibitors , RAW 264.7 Cells , Signal Transduction
2.
Biofizika ; 59(5): 887-94, 2014.
Article in Russian | MEDLINE | ID: mdl-25730969

ABSTRACT

Homology of the amino acid sequence of the mitochondrial potassium-transporting protein (MW 57kDa), having the properties of a channel subunit of the mitochondrial ATP-dependent potassium channel, and calreticulin (MW 55kDa) was detected by MALDI-TOF-TOF analysis method. Inhibitory analysis of ATP-dependent potassium transport in mitochondria with polyclonal antibodies to calreticulin was carried out. A dose-dependent inhibition of potassium transport in mitochondria by these antibodies was shown. The maximum value of inhibition was 55-60%. Based on these data it is hypothesized that at least two types of ATP-sensitive potassium channels are localized in mitochdndrial membrane. It is expected that the type of mitochondrial ATP-dependent potassium channel, which includes homologous calreticulin protein is localized mainly at mitochondrial and reticulum membrane contact sites.


Subject(s)
Adenosine Triphosphatases/metabolism , Calbindin 2/metabolism , Cation Transport Proteins/metabolism , Mitochondria, Liver/metabolism , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/metabolism , Animals , Antibodies/pharmacology , Calbindin 2/antagonists & inhibitors , Male , Mitochondrial Proteins/antagonists & inhibitors , Rats , Rats, Wistar , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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