Progressive, irreversible fibrosis is one of the most clinically significant consequences of ionizing radiation on normal tissue. When applied to lungs, it leads to a complication described as idiopathic pneumonia syndrome (IPS) and eventually to organ fibrosis. For its high mortality, the condition precludes treatment with high doses of radiation. There is widespread interest to understand the pathogenetic mechanisms of IPS and to find drugs effective in the prevention of its development. This report summarizes our experience with the protective effects of L 158,809, an angiotensin II (ANG II) receptor blocker, and two angiotensin converting enzyme (ACE) inhibitors in the development of IPS and the role of transforming growth factor beta (TGF-beta) and of alpha-actomyosin (alpha SMA) in pathogenesis of radiation induced pulmonary fibrosis in an experimental model of bone marrow transplant (BMT). Male WAG/Riji/MCV rats received total body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. While one group of animals remained untreated, the remainders were subdivided into three groups, each of them receiving either the ANG II receptor blocker or one of the two ACE inhibitors (Captopril or Enalapril). Each of the three drugs was administered orally from 11 days before the transplant up to 56 days post transplant. At sacrifice time the irradiated rats receiving only CTX showed a chronic pneumonitis with septal fibrosis and vasculitis affecting, in particular, small caliber pulmonary arteries and arterioles. Their lung content of hydroxyproline was also markedly elevated in association with the lung concentrations of thromboxane (TXA2) and prostaglandin (PGI(2)), (two markers of pulmonary endothelial damage). A significant increase of alpha actomyosin staining was observed in vessels, septa and macrophages of the same animals which also overexpressed TGF-beta. When L 158,809, Captopril and Enalapril were added to the radiation and cytoxan treatment, a significant amelioration of the histological damage as well as the overexpression of alpha SMA was observed. Lung concentrations of hydroxyproline, PGI(2), TXA2 and TGF-beta were also observed in these animals so that the values of these compounds were closer to those measured in untreated control rats than to their irradiated and cytoxan treated counterparts. Angiotensin II plays an important role in the regulation of TGF-beta and alpha SMA, two proteins involved in the pathogenesis of pulmonary fibrosis. The finding that ACE inhibitors or ANG II receptor blockers protect the lungs from radiation induced pneumonitis and fibrosis reaffirms the role that ANG II plays in this inflammatory process and suggests an additional indication of treatment of this condition, thus opening a new potential pharmacologic use of these drugs.
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http://dx.doi.org/10.2174/138161207780618777 | DOI Listing |
Int J Immunopathol Pharmacol
December 2024
Clinical Pathology Department, Veterinary Medicine Faculty, University of Mansoura, Mansoura, Egypt.
Our study intended to explore Hesp antioxidant and anti-inflammatory effects against TAA hepatic fibrosis in rats. Hesperidin (Hesp), is a pharmacologically active flavonoid, found abundantly in citrus species. Our present research attempts to inspect the potential hepatoprotective role of Hesp against thioacetamide (TAA)-induced hepatic fibrosis.
View Article and Find Full Text PDFCell Biol Toxicol
December 2024
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 13850 E. Montview Blvd, Box C238/V20-3128, Aurora, CO, 80045, USA.
Toxicant exposure can lead to acute liver injury, characterized by hepatic reprogramming and wound healing. Hepatic stellate cells (HSC) play a key role in liver regeneration during wound healing by secreting fibrogenic factors and production of extracellular matrix (ECM). However, repetitive injury to the liver can lead to extensive scarring and liver fibrosis, indicating HSCs coordinate both regeneration and disease.
View Article and Find Full Text PDFTissue Cell
December 2024
School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), Polepally SEZ, TSIIC, Jadcherla, Mahbubnagar, Hyderabad 509301, India.
In this study, we investigated the efficacy of oxymatrine, a phytochemical alkaloid, in reducing inflammation and fibrosis in a rat model of IgA nephropathy (IgAN) through modulation of the TGF-β/SMAD signaling pathway. Thirty Sprague Dawley rats were randomized into control, IgAN, and treatment groups, the latter receiving oxymatrine postinduction of IgAN. Induced by bovine serum albumin, carbon tetrachloride, and lipopolysaccharides, the disease model was validated by immunofluorescence and histopathological analyses, confirming significant renal deposition of IgA and increased fibrosis markers (IL-6, TGF-β, SMAD 3, and α-SMA).
View Article and Find Full Text PDFAnatol J Cardiol
December 2024
Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Background: Cardiac fibrosis, a key contributor to heart failure, is driven by the activation of cardiac fibroblasts (CFs), often induced by angiotensin II (Ang II). Relaxin, a peptide hormone, has been reported to counteract fibrotic processes. This study aims to investigate the antifibrotic effects of relaxin on Ang II-induced CF activation, with a focus on the involvement of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway.
View Article and Find Full Text PDFFront Physiol
December 2024
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, United States.
Introduction: Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (, phrenic) motor neuron death and mimics aspects of motor neuron disease [(, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (.
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