Abstract
Bleomycin-induced lung inflammation and fibrosis were assessed in a model of idiopathic pulmonary fibrosis in C57BL/6 mice and effect of spiperone on histopathological lung indicators, hematopoietic (HSC) and mesenchymal (MSC) stem cells and progenitor cells was characterized. Spiperone is a selective antagonist of D2 dopamine receptors which disturbs dopamine mediation. Hematoxylin and eosin staining showed spiperone decreased alveolar epithelial edema, exudation and infiltration of the alveoli walls and lumen by inflammatory cells (neutrophils, macrophages, plasma cells) after bleomycin instillation. Picrofuchsin staining by Van Gieson revealed spiperone decreases the area of connective tissue in the lung fibrotic phase of pulmonary fibrosis. ELISA assay determined the decrease levels of collagen type I, hydroxyproline and total collagen in lung homogenate after spiperone treatment. Number of “long-term” HSCs (Lin- Sca-1+c-Kit+CD34-), «short-term” HSCs (Lin-Sca-1+c-Kit+CD34+), hematopoietic progenitor cells and MSC-like cells in lung with pneumofibrosis decreased after spiperone treatment. This spiperone effect we connect to the violation of immature bone marrow cells migration. Additionally, spiperone inhibited clonal activity of hematopoietic (CFU-GEMM, CFU-G) and mesenchymal (CFU-F) progenitor of bone marrow, blood and lungs. An additional feature of the spiperone action was the ability to decrease the capacity of self-renewal and MSCs differentiation activity into adipocytes, osteoblasts, chondrocytes and fibroblast cells. Thus, a selective antagonist D2 of dopamine receptors spiperone can act as a potential antifibrotic agent for the treatment of toxic pulmonary fibrosis. The overall conclusion was that the neurotropic agent spiperone is able to influence the stem and progenitor cells in lung pathology effectively.
Highlights
Idiopathic pulmonary fibrosis is a chronic actively progressive disease of unknown etiology
We have previously shown that sympatholytic reserpine affects hematopoietic stem cells (HSCs) and hematopoietic progenitor cells, which resulted in a decrease in pulmonary fibrosis [15]
The objectives of this study were: 1) to assess whether spiperone decrease the development of bleomycin-induced pulmonary fibrosis in C57BL/6 mice; 2) to study the effect of spiperone on HSCs and mesenchymal stem cells (MSCs) and progenitor cells in pulmonary fibrosis
Summary
Idiopathic pulmonary fibrosis is a chronic actively progressive disease of unknown etiology. The cause of Parkinson’s disease, schizophrenia, autism, attention deficit, hyperactivity disorder, and drug abuse are associated with dopamine deficit. Dopamine D1 and D2 receptor subtypes of the central nervous system are characterized pharmacologically and biochemically [6]. It is known that dopamine D2 receptors are involved in the pathophysiology of Parkinson’s disease, Alzheimer’s disease and schizophrenia [7]. Dopamine and dopamine receptors (D1-4 subtypes) are determined in lung tissue [9]. Dopamine D1 and D2 receptor subtypes are described in lung vessels [10,11]. We do not exclude that dopamine and dopamine receptors may be involved in the pathophysiology of pulmonary disorders, including the pathophysiology of idiopathic pulmonary fibrosis
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