ABSTRACT
Mutations in lipase H (LIPH) and lysophosphatidic acid receptor 6 (LPAR6), which are essential for the lysophosphatidic acid (LPA) signalling pathway, are associated with hypotrichosis and wooly hair in humans. Mutations in LPAR6 and keratin 71 (KRT71), result in unusual fur growth and hair structure in several cat breeds (Cornish Rex, Devon Rex and Selkirk Rex). Here, we performed target sequencing of the LIPH, LPAR6 and KRT71 genes in six cat breeds with specific hair-growth phenotypes. A LIPH genetic variant (LIPH:c.478_483del; LIPH:p.Ser160_Gly161del) was found in Ural Rex cats with curly coats from Russia, but was absent in all other cat breeds tested. In silico three-dimensional analysis of the LIPH mutant protein revealed a contraction of the α3-helix structure in the enzyme phospholipid binding site that may affect its activity.
Subject(s)
Cats/genetics , Hair/anatomy & histology , Keratins, Hair-Specific/genetics , Lipase/genetics , Mutation , Receptors, Lysophosphatidic Acid/genetics , Animals , Keratins, Hair-Specific/metabolism , Lipase/metabolism , Mutant Proteins/genetics , Mutant Proteins/metabolism , Receptors, Lysophosphatidic Acid/metabolism , Species SpecificityABSTRACT
The study of the influence of cobra Naja oxiana cardiotoxins on the contractility of the rat papillary muscles and its rhythmoinotropic characteristics has shown that the presence of toxins induces a slight contractility decrease in the stimulation frequency range up to 0.1 Hz. In the stimulation frequency range from 0.1 to 0.5 Hz, a positive inotropic effect is found. However, the positive inotropic effect is replaced by a negative one with further increase in the frequency up to 3 Hz. In the presence of cardiotoxins, the positive force-frequency relationship in the region of 1-3 Hz, characteristic of healthy rat myocardium, disappears and the relationship becomes completely negative. L-type calcium channel blocker nifedipine does not affect the changes induced by toxins, while a high concentration (10 mM) of calcium prevents the effects of cardiotoxins on the muscle. The results obtained show that the impairment of the force-frequency relationship occurs long before the development of irreversible damage in the myocardium and may be the first sign of the pathological action of cardiotoxins.
Subject(s)
Cobra Cardiotoxin Proteins/pharmacology , Heart/drug effects , Heart/physiology , Myocardial Contraction/drug effects , Naja naja , Animals , Dose-Response Relationship, Drug , RatsABSTRACT
Four dimeric disintegrins were isolated from the venom of the steppe viper V. ursinii using liquid chromatography. Disintegrins prevented adhesion of MCF7 cells to fibronectin, which indicates their interaction with integrin receptors of the αVß1 type. According to mass spectrometry data, the molar masses of disintegrins are about 14 kDa. The method of peptide mapping established the structure of a new heterodimeric disintegrin weighing 13 995.5 Da and shows that it belongs to the class of RGD/KGD-containing disintegrins.
Subject(s)
Disintegrins/chemistry , Protein Multimerization , Reptilian Proteins/chemistry , Viper Venoms/chemistry , Viperidae , Animals , Disintegrins/pharmacology , Humans , MCF-7 Cells , Receptors, Vitronectin/metabolism , Reptilian Proteins/pharmacology , Viper Venoms/pharmacologyABSTRACT
An increase in the life expectancy during the last decades in most world countries has resulted in the growing number of people suffering from neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and others. Familial forms of neurodegenerative diseases account for 5-10% of all cases and are caused by mutations in specific genes often resulting in pathological protein deposition. The risk factors for neurodegeneration include trauma, lifestyle, and allelic variants of disease-associated genes with incomplete penetrance. Many of these gene variants are located in immunity-related loci, particularly in the human leukocyte antigen locus (HLA class II) coding for proteins of the major histocompatibility complex class II (MHCII). HLA class II plays a key role in the antigen presentation and is expressed in microglial cells. Microglia is a component of innate immunity. On the one hand, microglial cells phagocytize pathological protein deposits; on the other hand, they produce proinflammatory factors accelerating neuronal death. The involvement of adaptive immunity mechanisms (antigen presentation, T cell response, antibody production) in the development of neurodegenerative diseases remains unclear and requires further research, including more detailed studies of the role of identified HLA class II genetic variants.
Subject(s)
Histocompatibility Antigens Class II/genetics , Neurodegenerative Diseases/pathology , Presenilins/genetics , Adaptive Immunity , Alzheimer Disease/genetics , Alzheimer Disease/immunology , Alzheimer Disease/pathology , HLA-DR alpha-Chains/genetics , HLA-DRB1 Chains/genetics , Histocompatibility Antigens Class II/metabolism , Humans , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/immunology , Parkinson Disease/genetics , Parkinson Disease/immunology , Parkinson Disease/pathology , Polymorphism, Single NucleotideABSTRACT
Aging and genetic predisposition are major risk factors in age-related neurodegenerative disorders. The most common neurodegenerative disorder is Alzheimer's disease (AD). Genome-wide association studies (GWAS) have identified statistically significant association of the PICALM rs3851179 polymorphism with AD. The PICALM G allele increases the risk of AD, while the A allele has a protective effect. We examined the association of the PICALM rs3851179 polymorphism with parameters of the P3 component of auditory event-related potentials (ERPs) in 87 non-demented volunteers (age, 19-77 years) subdivided into two cohorts younger and older than 50 years of age. We found statistically significant association between the AD risk variant PICALM GG and increase in the P3 latency in subjects over 50 years old. The age-dependent increase in the P3 latency was more pronounced in the PICALM GG carriers than in the carriers of the PICALM AA and PICALM AG genotypes. The observed PICALM-associated changes in the neurophysiological processes indicate a decline in the information processing speed with aging due, probably, to neuronal dysfunction and subclinical neurodegeneration of the neuronal networks in the hippocampus and the frontal and parietal cortical areas. Such changes were less pronounced in the carriers of the PICALM gene A allele, which might explain the protective effect of this allele in the cognitive decline and AD development.
Subject(s)
Aging/genetics , Alzheimer Disease/pathology , Evoked Potentials/physiology , Monomeric Clathrin Assembly Proteins/genetics , Adult , Aged , Alleles , Alzheimer Disease/genetics , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Young AdultABSTRACT
Genes encoding two three-finger toxins TFT-AF and TFT-VN, nucleotide sequences of which were earlier determined by cloning cDNA from venom glands of vipers Azemiops feae and Vipera nikolskii, respectively, were expressed for the first time in E. coli cells. The biological activity of these toxins was studied by electrophysiological techniques, calcium imaging, and radioligand analysis. It was shown for the first time that viper three-finger toxins are antagonists of nicotinic acetylcholine receptors of neuronal and muscle type.
Subject(s)
Muscles/metabolism , Neurons/metabolism , Receptors, Nicotinic/metabolism , Recombinant Proteins/metabolism , Toxins, Biological/metabolism , Viperidae/genetics , Animals , Calcium Signaling , Cell Line, Tumor , Humans , Muscles/cytology , Neurons/cytology , Recombinant Proteins/genetics , Toxins, Biological/geneticsABSTRACT
Turritopsis dohrnii (Cnidaria, Hydrozoa, Hydroidolina, Anthoathecata) is the only known metazoan that is capable of reversing its life cycle via morph rejuvenation from the adult medusa stage to the juvenile polyp stage. Here, we present a complete mitochondrial (mt) genome sequence of T. dohrnii, which harbors genes for 13 proteins, two transfer RNAs, and two ribosomal RNAs. The T. dohrnii mt genome is characterized by typical features of species in the Hydroidolina subclass, such as a high A+T content (71.5%), reversed transcriptional orientation for the large rRNA subunit gene, and paucity of CGN codons. An incomplete complementary duplicate of the cox1 gene was found at the 5' end of the T. dohrnii mt chromosome, as were variable repeat regions flanking the chromosome. We identified species-specific variations (nad5, nad6, cob, and cox1 genes) and putative selective constraints (atp8, nad1, nad2, and nad5 genes) in the mt genes of T. dohrnii, and predicted alterations in tertiary structures of respiratory chain proteins (NADH4, NADH5, and COX1 proteins) of T. dohrnii. Based on comparative analyses of available hydrozoan mt genomes, we also determined the taxonomic relationships of T. dohrnii, recovering Filifera IV as a paraphyletic taxon, and assessed intraspecific diversity of various Hydrozoa species.
Subject(s)
Biological Evolution , Genome, Mitochondrial , Life Cycle Stages/genetics , Scyphozoa/growth & development , Scyphozoa/genetics , Animals , Base Sequence , DNA, Mitochondrial/genetics , Genes, Mitochondrial , Genetic Variation , Nucleotides/genetics , Open Reading Frames/genetics , Phylogeny , RNA, Ribosomal/geneticsABSTRACT
Certain cellular proteins normally soluble in the living organism under certain conditions form aggregates with a specific cross-ß sheet structure called amyloid. These intra- or extracellular insoluble aggregates (fibers or plaques) are hallmarks of many neurodegenerative pathologies including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, prion disease, and other progressive neurological diseases that develop in the aging human central nervous system. Amyloid diseases (amyloidoses) are widespread in the elderly human population, a rapidly expanding demographic in many global populations. Increasing age is the most significant risk factor for neurodegenerative diseases associated with amyloid plaques. To date, nearly three dozen different misfolded proteins targeting brain and other organs have been identified in amyloid diseases and AD, the most prevalent neurodegenerative amyloid disease affecting over 15 million people worldwide. Here we (i) highlight the latest data on mechanisms of amyloid formation and further discuss a hypothesis on the amyloid cascade as a primary mechanism of AD pathogenesis and (ii) review the evolutionary aspects of amyloidosis, which allow new insight on human-specific mechanisms of dementia development.
Subject(s)
Aging/metabolism , Alzheimer Disease/metabolism , Amyloid/metabolism , Age Factors , Aging/pathology , Alzheimer Disease/epidemiology , Alzheimer Disease/pathology , Animals , Humans , Risk FactorsABSTRACT
LINE1 retrotransposons are members of a class of mobile genetic elements capable of retrotransposition in the genome via a process of reverse transcription. LINE1 repeats, integrating into different chromosomal loci, affect the activity of genes and cause different genomic mutations. Somatic variability of the human genome is linked to the activity of some subfamilies of LINE1, in particular, a high level of LINE1 retrotranspositions has been observed in brain tissues. However, the contribution of LINE1 to genomic variability during normal aging and in age-related neurodegenerative diseases is poorly understood. We conducted quantitative real-time PCR analysis of active subfamilies of LINE1 repeats (aL1) using genomic DNA extracted from brain specimens of Alzheimer's disease (AD) patients and individuals without neuropsychiatric pathologies, as well as DNA extracted from blood specimens of individuals of different ages (healthy and AD subjects). Inter-individual quantitative variations of active families of aL1 repeats in the genome were observed. No significant age-dependent differences were identified. Likewise, no difference of aL1 copy number in brain and blood were indicated between AD patients and the aged-matched control group without dementia. These data imply that aging and the AD-associated neurodegenerative process are not the major factors contributing to the retrotransposition processes of active LINE1 repeats.
Subject(s)
Aging , Alzheimer Disease/pathology , Long Interspersed Nucleotide Elements/genetics , 5' Untranslated Regions , Aged , Alzheimer Disease/metabolism , Case-Control Studies , Female , Frontal Lobe/metabolism , Genome, Human , Humans , Male , Middle Aged , RNA, Ribosomal, 5S/genetics , RNA, Ribosomal, 5S/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
Nonconventional three-finger toxin BMLCL was isolated from B. multicinctus venom, and its interaction with different subtypes of nicotinic acetylcholine receptor (nAChR) was studied. It was found that BMLCL is able to interact with high efficiency with both α7 and muscle type nAChRs.
Subject(s)
Bungarotoxins/metabolism , Bungarotoxins/pharmacology , Cholinergic Agents/pharmacology , Receptors, Nicotinic/metabolism , Reptilian Proteins/metabolism , Reptilian Proteins/pharmacology , Acetylcholine/pharmacology , Amino Acid Sequence , Animals , Aplysia , Bungarotoxins/chemistry , Bungarotoxins/isolation & purification , Bungarus , Cholinergic Agents/chemistry , Cholinergic Agents/isolation & purification , Cholinergic Agents/metabolism , Cobra Neurotoxin Proteins/pharmacology , Humans , Lymnaea , Membrane Potentials/drug effects , Membrane Potentials/physiology , Molecular Sequence Data , Oocytes , Rats , Reptilian Proteins/chemistry , Reptilian Proteins/isolation & purification , Sequence Homology, Amino Acid , XenopusABSTRACT
A total of 40 patients (median age 6 years, range 1-28 years) with high-risk malignant brain tumors received a single (n = 35) or tandem (n = 5) high-dose chemotherapy (HDCT) with autologous hemopoietic stem cell transplantation (auto-HSCT). The 2-year OS and DFS are 52% and 47%, accordingly, with median follow-up of 24 (range 2-96) months. The patients without complete response at the time of auto-HSCT had worst prognosis with 53% DFS in patients with partial remission and 25% in patients with disease stabilization (p = 0.001). Patients with relapsed tumor had worse prognosis, than high-risk patients in the first remission with DFS 26% and 62%, accordingly (p=0.02). The relapse rate also correlated with patient's age (38% DFS in patients younger, than 4 years and 60% in older patients, p = 0.005) and tumor morphology (63% DFS in patients with medulloblastoma, 60% in patients with germ-cell tumors, 45% in other embryonal CNS tumors, p = 0.05). The 4th-grade transplant-related toxicity and mortality rates were observed in 13% and 18% of patients, accordingly. Therefore, HDCT with auto-HSCT in young patients with high-risk CNS tumors is characterized by acceptable toxicity and allows improving overall therapy results.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/pathology , Brain Neoplasms/prevention & control , Brain Neoplasms/surgery , Child , Child, Preschool , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Kaplan-Meier Estimate , Male , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Prognosis , Transplantation, Autologous , Treatment Outcome , Young AdultABSTRACT
A biological microchip (biochip) for the genetic predis- position to sporadic form of Alzheimer's disease studying has been developed. The biochip allows determina- tion of ten genetic polymorphisms within APOE, TOMM40, APOJ, EXOC3L2, GAB2, A2M, CR1, BIN1 and PICALM genes. The genotyping assay includes the amplification of loci of interest and further allele-specific hybridization of the fluorescent labeled amplicons with oligonucleotides immobilized on a biochip. Based on the results of genotyping of 166 patients and 128 controls APOE epsilon4 allele was found to be significantly associated with Alzheimer's disease susceptibility (OR = 2.275, 95% CI = 1.045-4.954,p = 0.034). Additionally, protective effects for the APOE epsilon2 allele and CLUT-allele (rs11136000) were observed (OR = 0.215, 95% CI = 0.090-0.516, p = 0.001 and OR = 0.679, 95% CI = 0.47-0.99, p = 0.042, respectively). Gene-gene interaction revealed two genotype combinations associated with Alzheimer's disease: APOE E3/E4 GAB2 G/G (OR = 2.49; CI = 1.43-4.32, p = 0.001) and APOE epsilon4 GAB2 G/G (OR = 3.55, CI = 1.23-10.24,p = 0.015). Based on the results of the combined multivariate analysis the algorithm for identifying of individuals at increased risk of Alzheimer's disease was developed.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Genetic Predisposition to Disease , Protein Array Analysis , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/pathology , Ethnicity/genetics , Female , Genetic Markers , Genotype , Humans , Male , Middle Aged , Protein Array Analysis/instrumentation , Protein Array Analysis/methods , Risk Factors , RussiaABSTRACT
The development of new biomarkers for prediction and early detection of human diseases, as well as for monitoring the response to therapy is one of the most relevant areas of modern human genetics and genomics. Until recently, it was believed that the function of human Y chromosome genes was limited to determining sex and controlling spermatogenesis. Thanks to occurance of large databases of the genome-wide association study (GWAS), there has been a transition to the use of large samples for analyzing genetic changes in both normal and pathological conditions. This has made it possible to assess the association of mosaic aneuploidy of the Y chromosome in somatic cells with a shorter lifespan in men compared to women. Based on data from the UK Biobank, an association was found between mosaic loss of the Y chromosome (mLOY) in peripheral blood leukocytes and the age of men over 70, as well as a number of oncological, cardiac, metabolic, neurodegenerative, and psychiatric diseases. As a result, mLOY in peripheral blood cells has been considered a potential marker of biological age in men and as a marker of certain age-related diseases. Currently, numerous associations have been identified between mLOY and genes based on GWAS and transcriptomes in affected tissues. However, the exact cause of mLOY and the impact and consequences of this phenomenon at the whole organism level have not been established. In particular, it is unclear whether aneuploidy of the Y chromosome in blood cells may affect the development of pathologies that manifest in other organs, such as the brain in Alzheimer's disease, or whether it is a neutral biomarker of general genomic instability. This review examines the main pathologies and genetic factors associated with mLOY, as well as the hypotheses regarding their interplay. Special attention is given to recent studies on mLOY in brain cells in Alzheimer's disease.
ABSTRACT
Catalepsy is a behavioral condition that is associated with severe psychopathologies, including schizophrenia, depression, and Parkinson's disease. In some mouse strains, catalepsy can be induced by pinching the skin at the scruff of the neck. The main locus of hereditary catalepsy in mice has recently been linked to the 105-115 Mb fragment of mouse chromosome 13 by QTL analysis. We performed whole-genome sequencing of catalepsy-resistant and catalepsy-prone mouse strains in order to pinpoint the putative candidate genes related to hereditary catalepsy in mice. We remapped the previously described main locus for hereditary catalepsy in mice to the chromosome region 103.92-106.16 Mb. A homologous human region on chromosome 5 includes genetic and epigenetic variants associated with schizophrenia. Furthermore, we identified a missense variant in catalepsy-prone strains within the Nln gene. Nln encodes neurolysin, which degrades neurotensin, a peptide reported to induce catalepsy in mice. Our data suggest that Nln is the most probable candidate for the role of major gene of hereditary, pinch-induced catalepsy in mice and point to a shared molecular pathway between catalepsy in mice and human neuropsychiatric disorders.
ABSTRACT
Effects of a sympatholytic drug on bone marrow stromal and hemopoietic precursors were studied on the model of cyclophosphamide-induced myelosuppression. Sympatholytic treatment increased the content of hemopoietic stem cells of different classes in the bone marrow. Selective stimulation of differentiation of polypotent precursors into granulocyte-macrophage precursors was noted. Acceleration of proliferation and maturation of granulocytic precursors was observed at later terms during regeneration of the hemopoietic tissue. The sympatholytic inhibited proliferation of stromal precursors and reduced feeder activity of fibroblasts for granulocyte precursors.
Subject(s)
Adrenergic Uptake Inhibitors/administration & dosage , Bone Marrow/drug effects , Catecholamines/antagonists & inhibitors , Hematopoietic Stem Cells/drug effects , Reserpine/administration & dosage , Stromal Cells/drug effects , Animals , Bone Marrow/metabolism , Catecholamines/metabolism , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Colony-Forming Units Assay , Cyclophosphamide/administration & dosage , Cytostatic Agents/administration & dosage , Granulocytes/drug effects , Granulocytes/metabolism , Hematopoietic Stem Cells/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred CBA , Multipotent Stem Cells/drug effects , Multipotent Stem Cells/metabolism , Myelopoiesis/drug effects , Stromal Cells/metabolismABSTRACT
The effect of a course treatment with a sympatholytic reserpine on the inflammatory response and connective tissue proliferation in the lungs of C57Bl/6 mice was studied on the model of toxic pulmonary fibrosis induced by intratracheal administration of bleomycin. This sympatholytic reduced infiltration of the alveolar interstitium and alveolar ducts with inflammatory cells (lymphocytes, macrophages, neutrophils, and plasma cells) and prevented connective tissue proliferation in the lungs. The anti-inflammatory effect of reserpine was associated with a decrease in activity of bone marrow granulocyte-erythroid-macrophage-megakaryocyte and granulocyte precursors (proliferation and mobilization). The antifibrotic effect of reserpine was due to a decrease in the number of committed precursors for mesenchymopoiesis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Bleomycin/toxicity , Pulmonary Alveoli/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Reserpine/pharmacology , Sympatholytics/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Colony-Forming Units Assay , Granulocyte-Macrophage Progenitor Cells/drug effects , Histological Techniques , Mice , Mice, Inbred C57BL , Neutrophil Infiltration/drug effects , Pulmonary Alveoli/immunology , Reserpine/therapeutic use , Statistics, Nonparametric , Sympatholytics/therapeutic useABSTRACT
Hemopoiesis-stimulating activity of immobilized oligonucleotide preparation was studied on the model of cytostatic myelosuppression induced by injection of cyclophosphamide and 5-fluorouracil. Immobilized oligonucleotides stimulated regeneration of erythro- and granulocytopoiesis in the bone marrow under conditions of cytostatic treatment. The counts of neutrophilic granulocytes and platelets in the peripheral blood increased. The stimulatory effect of the drug was more manifest in animals with active behavior. The mechanism of immobilized oligonucleotide effect was based on stimulation of functional activity of erythroid and granulocytic macrophage precursors.
Subject(s)
Erythropoiesis/drug effects , Hematinics/administration & dosage , Myelopoiesis/drug effects , Oligonucleotides/administration & dosage , Administration, Oral , Animals , Blood Platelets/cytology , Blood Platelets/drug effects , Bone Marrow/drug effects , Bone Marrow/physiology , Cell Count , Cyclophosphamide/administration & dosage , Cytostatic Agents/administration & dosage , Erythropoiesis/physiology , Fluorouracil/administration & dosage , Granulocytes/cytology , Granulocytes/drug effects , Hematinics/chemistry , Injections, Intraperitoneal , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Mice , Mice, Inbred CBA , Myelopoiesis/physiology , Oligonucleotides/chemistryABSTRACT
The effects of antiserotonin preparation on the development of the connective tissue in the lungs, reaction of the blood system, and the content of hemopoietic stem cells, committed hemopoietic and stromal precursors in BM, spleen, and peripheral blood were studied on C57Bl/6 mice with experimental toxic lung fibrosis caused by intratracheal administration of bleomycin. It was demonstrated that the antiserotonin drug inhibits the growth of the connective tissue in the lungs and attenuates the course inflammatory process primarily due to inhibition of the granulocytic lineage, which was related to suppression of hemopoietic stem cells. Reduced content of the stromal precursor cells in BM and spleen was noted.
Subject(s)
Cyproheptadine/administration & dosage , Lung/drug effects , Pulmonary Fibrosis/drug therapy , Serotonin Antagonists/administration & dosage , Animals , Bleomycin/administration & dosage , Bone Marrow/drug effects , Bone Marrow/metabolism , Bone Marrow/pathology , Granulocytes/drug effects , Granulocytes/pathology , Injections, Intraperitoneal , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Spleen/drug effects , Spleen/metabolism , Spleen/pathology , Stromal Cells/drug effects , Stromal Cells/pathologyABSTRACT
The effect of course treatment with neuroleptic haloperidol on the inflammatory response and state of the connective tissue in the lungs of C57Bl/6 mice was studied on the model of toxic pulmonary fibrosis induced by intratracheal administration of bleomycin. This neuroleptic decreased the inflammatory response and reduced the growth of the connective tissue in the lungs. The anti-inflammatory effect of haloperidol is related to a decrease in activity of bone marrow hemopoietic stem cells and committed hemopoietic precursors. The antifibrotic effect of this drug is associated with inhibition of mesenchymal precursor cells.
Subject(s)
Antipsychotic Agents/administration & dosage , Connective Tissue/pathology , Haloperidol/administration & dosage , Inflammation/drug therapy , Lung/pathology , Pulmonary Fibrosis/drug therapy , Administration, Inhalation , Animals , Bleomycin/administration & dosage , Cell Differentiation/drug effects , Connective Tissue/drug effects , Disease Models, Animal , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/pathology , Inflammation/chemically induced , Inflammation/complications , Inflammation/pathology , Lung/drug effects , Lymphocyte Count , Lymphocytes/cytology , Lymphocytes/drug effects , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/pathology , Mice , Mice, Inbred C57BL , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/pathologyABSTRACT
The influence of granulocyte colony-stimulating factor (G-CSF) has been studied on a model of bleomycin-induced pulmonary fibrosis. It is established that G-CSF significantly increases infiltration of alveolar and alveolar duct interstitium by inflammation cells (lymphocytes, neutrophils, plasmocytes) and increases collagen deposition in lung under conditions of bleomycin introduction. Simultaneously with profibrotic and anti-inflammation effects, G-CSF increased the content of granulocyte cells in the bone marrow and peripheral blood, which was related to the stimulation of committed granulocyte precursors in the bone marrow.