Biomedical subjects

K Sokol

Publications and source records attributed to K Sokol.

At least 19 recordsLinked to original sources

PubMed1997

Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development.

We recently have shown that mice deficient for the 86-kDa component (Ku80) of the DNA-dependent protein kinase exhibit growth retardation and a profound deficiency in V(D)J (variable, diversity, and joining) recombination. These defects may be related to abnormalities in DNA metabolism that arise from the inability of Ku80 mutant cells to process DNA double-strand breaks. To further characterize the role of Ku80 in DNA double-strand break repair, we have generated embryonic stem cells and pre-B cells and examined their response to ionizing radiation. Ku80(-/-) embryonic stem cells are more sensitive than controls to gamma-irradiation, and pre-B cells derived from Ku80 mutant mice display enhanced spontaneous and gamma-ray-induced apoptosis. We then determined the effects of ionizing radiation on the survival, growth, and lymphocyte development in Ku80-deficient mice. Ku80(-/-) mice display a hypersensitivity to gamma-irradiation, characterized by loss of hair pigmentation, severe injury to the gastrointestinal tract, and enhanced mortality. Exposure of newborn Ku80(-/-) mice to sublethal doses of ionizing radiation enhances their growth retardation and results in the induction of T cell-specific differentiation. However, unlike severe combined immunodeficient mice, radiation-induced T cell development in Ku80(-/-) mice is not accompanied by extensive thymocyte proliferation. The response of Ku80-deficient cell lines and mice to DNA-damaging agents provides important insights into the role of Ku80 in growth regulation, lymphocyte development, and DNA repair.

Animals↗

PubMed1997

Oligosaccharides interfere with the establishment and progression of experimental pneumococcal pneumonia.

Oligosaccharides that block the adherence of bacteria to epithelial cells in vitro--lacto-N-neotetraose (LNnT) and its alpha2-3- and alpha2-6-sialylated derivatives--were tested for their abilities to attenuate the course of pneumococcal pneumonia and to prevent colonization of the nasopharynx in animal models. Intratracheal administration of these agents concurrently with bacteria dramatically decreased pneumococcal load in the lungs of rabbits and conferred protection from bacteremia. The oligosaccharides ameliorated pneumonia and bacteremia when given therapeutically 24 h after infection was established. When administered intranasally, neoglycoconjugates of the active oligosaccharides prevented colonization of the nasopharynx of infant rats. In addition to in vitro anti-adherence properties, LNnT acted directly on cultured lung epithelial cell lines to induce changes such that pneumococcal adherence was prevented for prolonged periods. These activities encourage continued development of oligosaccharides as a class of potentially preventive and therapeutic agents for infectious diseases.

Animals↗

PubMed1996

Requirement for Ku80 in growth and immunoglobulin V(D)J recombination.

The DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threonine kinase that is implicated in the repair of DNA double-strand breaks, DNA replication, transcription, and V(D)J recombination. To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice. In mutant mice, T and B lymphocyte development is arrested at early progenitor stages and there is a profound deficiency in V(D)J rearrangement. Although Ku80-/- mice are viable and reproduce, they are 40-60% of the size of littermate controls. Consistent with this growth defect, fibroblasts derived from Ku80-/- embryos showed an early loss of proliferating cells, a prolonged doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle. The unexpected growth phenotype suggests a new and important link between Ku80 and growth control.

Animals↗

PubMed1995

Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase.

Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock. iNOS-/-mice failed to restrain the replication of Listeria monocytogenes in vivo or lymphoma cells in vitro. Bacterial endotoxic lipopolysaccharide (LPS) caused shock and death in anesthetized wild-type mice, but in iNOS-/-mice, the fall in central arterial blood pressure was markedly attenuated and early death averted. However, unanesthetized iNOS-/-mice suffered as much LPS-induced liver damage as wild type, and when primed with Propionobacterium acnes and challenged with LPS, they succumbed at the same rate as wild type. Thus, there exist both iNOS-dependent and iNOS-independent routes to LPS-induced hypotension and death.

Amino Acid Oxidoreductases↗

PubMed1995

Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor.

An immature v-abl-transformed mast cell line (V3-MC) was derived from a mouse that developed systemic mastocytosis after transplantation of v-abl-infected bone marrow cells. V3-MCs injected intravenously into adult BALB/c mice infiltrated the liver, spleen, and intestine by day 6 and underwent progressive differentiation and maturation, eventually resembling indigenous mast cells. In terms of their protease content, the V3-MCs that localized in the liver and spleen differed from those in the intestine, and both differed from the cultured V3-MCs. The acquired expression of certain proteases and the loss of expression of other proteases in these tissue V3-MCs defines particular phenotypes and indicates that the differentiation and maturation of mast cell-committed progenitor cells are primarily regulated by factors in the different tissue microenvironments.

Animals↗

PubMed1995

Effect of thalidomide on the inflammatory response in cerebrospinal fluid in experimental bacterial meningitis.

In experimental bacterial meningitis in rabbits, the inflammatory process is largely mediated by cytokines such as IL-1 and TNF-alpha. Since thalidomide has been shown to inhibit TNF-alpha production, experiments were carried out to determine whether the drug can modulate the inflammatory response to either lysates of H. influenzae (gram negative) or heat killed S. pneumoniae (gram positive) in rabbits. The introduction of a lysate of H. influenzae into the CSF of rabbits causes a very acute inflammatory response, as indicated by a rapid increase in TNF-alpha levels in the CSF and a concomitantly rapid leukocytosis. In contrast, the introduction of heat killed S. pneumoniae, induces a more indolent inflammatory response which also wanes more slowly. Thalidomide treatment reduces TNF-alpha production in both experimental systems, but has a greater effect on the more indolent gram positive inflammatory response in which peak TNF-alpha levels in the CSF are reduced by > 50%. Also, a sustained inhibition of leukocytosis is observed in the inflammatory response to heat-killed gram positive bacteria. In meningeal inflammation induced by the Gram negative lysate, treatment with thalidomide results in only a 29% inhibition of TNF-alpha release into the CSF. In contrast to the drug effect on TNF-alpha, thalidomide treatment does not significantly affect IL-1 levels in these models of rabbit bacterial meningitis.

Animals↗

PubMed1994