Disease relevance of Paf

• An unusual feature of Paf is that either the mutation itself or an inseparable chromosomal abnormality causes delayed disjunction of the X and Y chromosomes at meiotic metaphase I, which in turn results in approximately 19% XO progeny and slightly less than 1% XXY progeny from Paf/Y males [1].
• In mice anaesthetized with urethane, Paf (1-30 micrograms kg-1) produced hypotension which was not clearly dose-related [2].
• It is suggested that bronchoconstriction, probably associated with cardiovascular effects, is a major determinant of the acute toxicity of Paf in mice [2].
• 5. Inhibition of NO synthase induction by Paf antagonists might afford therapeutic benefits in the management of septic shock and possibly other cardiovascular disorders [3].

High impact information on Paf

• About 12-17% of the embryos obtained by mating mice carrying the In(X)1H or Paf mutations are of the 39,X (X0) genotype [4].
• The Paf mutation also alters the normal segregation of the X and the Y chromosomes during male meiosis by causing nondisjunction at anaphase I [5].
• Analysis of 1139 female meioses from an intersubspecific backcross using 15 PCR-based markers localizes Paf to an approximately 0.2-cM interval that includes the pseudoautosomal boundary [5].
• Propranolol (0.01-10 mg kg-1, i.p.) potentiated the effects of an LD20 of Paf dose-dependently, while the beta 1-adrenoceptor selective antagonist, metoprolol, was three orders of magnitude less potent in this respect [2].
• It may be concluded that pharmacological manipulation of beta 2-adrenoceptors modulates Paf-induced death in mice, while arachidonate metabolites of the cyclo-oxygenase pathway and peptidoleukotrienes do not appear to be involved [2].

Chemical compound and disease context of Paf

• 1. Nitric oxide (NO) synthase inhibitors and Paf antagonists abrogate hypotension in septic shock [3].

Biological context of Paf

• It has previously been reported that 19% of the daughters of males carrying the X-linked mutation patchy fur (Paf) are XO with a maternally derived X chromosome [6].
• This can be explained if the Paf mutation is a hypomorphic mutation that escapes X inactivation because, unlike the wild type allele, it is now located within the PAR [6].
• We hypothesize that the Paf mutation is associated with an inversion spanning the pseudoautosomal region (PAR) boundary, and that this leads to preferential crossing over between the resulting inverted region of PAR and an equivalent inverted PAR region within the compound Y* PAR [6].
• Patchy fur (Paf), a semidominant X-linked gene associated with a high level of X-Y nondisjunction in male mice [1].
• Intravenous Paf-acether (Paf, 15-80 micrograms kg-1) killed conscious Swiss mice in a dose-dependent manner, without causing platelet aggregation in the lung microvasculature, or pulmonary oedema [2].

Anatomical context of Paf

• Paf antagonists block induction of nitric oxide synthase in cultured macrophages and vascular smooth muscle cells [3].
• 2. A murine macrophage cell line (J774.2) and rat vascular smooth muscle cells (VSMC) were stimulated with lipopolysaccharide (LPS), either alone or in combination with Paf or Paf antagonists, BN 50739 or E-6123 [3].
• Non-specific Paf binding might have some physiological relevance when Paf metabolites interfere with prostacyclin synthesis, for example, in umbilical vein endothelial cells [7].

Associations of Paf with chemical compounds

• Salbutamol (1 mg kg-1, i.p.) provided complete protection against an LD80 of Paf [2].
• Dexamethasone (1-5 mg kg-1, s.c.) exerted a dose-dependent protection, when administered at least 4 h before Paf [2].
• High doses of indomethacin, aspirin, benoxaprofen and FPL 55712 given i.p. failed to inhibit the effects of an LD80 of Paf, while BW 755C (50-100 mg kg-1) exerted a dose-dependent protection and benzydamine (50 mg kg-1) and nordihydroguaiaretic acid (200 mg kg-1) were partially active [2].
• 4. BN 50739 (10 mumol/L and E-6123 (1 mumol#L) both reduced the expression of calcium-independent NO synthase activity and nitrite accumulation, while Paf alone had no effect [3].

References