Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with advanced liver disease, decreases in renal blood flow, glomerular filtration rate, and urinary output are frequently observed. The deterioration in renal function is usually not due to a unique cause but is the result of the concerted action of several mechanisms operating in parallel; decreased plasma protein formation and increased intrahepatic vascular resistance lead to sequestration of blood volume, favoring hypovolemia and reduction in cardiac output. At the same time enhanced formation of nitroxide leads to peripheral vasodilation; bacterial endotoxin escaping clearance by the diseased liver stimulates the expression of a long-acting nitroxide synthase. Furthermore, vasodilating intestinal mediators such as substance P escape inactivation by the liver. In the face of peripheral vasodilation the maintenance of blood pressure requires an increase in cardiac output, which is achieved by activation of sympathetic nervous tone, renal vasoconstriction, enhanced release of renin, angiotensin, aldosterone, and antidiuretic hormone, leading to renal retention of sodium and water. Renal vasoconstriction is opposed by vasodilatatory prostaglandins, and renal failure may be triggered by inhibition of prostaglandin formation. On the other hand, vasoconstrictive eicosanoids, such as thromboxane B2 and leukotriene E2, which escape hepatic inactivation, may contribute to renal vasoconstriction. Beyond these mechanisms disturbed hepatic regulation of renal function may participate in the generation of hepatorenal syndrome. The liver regulates renal function via both a hepatorenal reflex decreasing renal blood flow and a hypothetical liver-borne diuretic factor increasing renal blood flow. Both enhanced hepatorenal reflex activity and decreased formation of the liver-borne diuretic factor could participate in the pathogenesis of hepatorenal syndrome.
 ...
PMID:New clues to the pathophysiology of hepatorenal failure. 846 32

The aim of this study was to determine whether neutral endopeptidase activity is elevated in serum in children with cholestatic liver disease (Alagille syndrome), and whether the enzyme cooperates with the serum aminopeptidase-M in degradation of peptides. Our data suggest that neutral endopeptidase activity remains at a very low level,.undetectable with the assays we have applied, both in the serum from healthy children and those with cholestasis. In contrast, the serum aminopeptidase-M activity is highly increased in cholestasis. We have demonstrated that aminopeptidase-M alone is capable of sequential and complete hydrolysis of enkephalins and low-molecular-weight, nonspecific peptides. The rate of release of free amino acids from both exogenous or endogenous substrate peptides was statistically significantly higher in serum in children with cholestasis compared with healthy children (P < 0.05). Substance P (Ki = 2.5 micromol/liter) and bradykinin (Ki = 27 micromol/liter) were shown to be potent inhibitors of the serum aminopeptidase-M. We postulate that aminopeptidase-M, except when regulating the activity of bioactive peptides, may serve as a scavenger of short, nonspecific peptides in the circulation. Our data seem to provide new insights for further studies on the role of serum peptidases both in physiology and pathophysiology.
 ...
PMID:Neutral endopeptidase activity is not elevated in serum in children with cholestatic liver disease: a unique role of aminopeptidase-m in sequential hydrolysis of peptides. 1218 28

Previously, we have shown that primary afferent sensory neurons are necessary for disease activity in T cell-mediated immune hepatitis in mice. In the present study, we analyzed the possible role of substance P (SP), an important proinflammatory neuropeptide of these nerve fibers, in an in vivo mouse model of liver inflammation. Liver injury was induced by bacterial lipopolysaccharide (LPS) in D-galactosamine (GalN)-sensitized mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment down-regulated circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) and protected mice from GalN/LPS-induced liver injury. Likewise, pretreatment of mice with antagonists of the SP-specific neurokinin-1 receptor (NK-1R), i.e., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060), dose dependently protected mice from GalN/LPS-induced liver injury. The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry. NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis. To get further insight into the mechanism by which receptor blockade attenuated GalN/LPS-induced liver damage, we analyzed plasma levels and intrahepatic expression of TNFalpha, IFNgamma, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFalpha and IFNgamma, whereas synthesis of the hepatoprotective cytokines IL-6 and IL-10 was increased. NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects.
 ...
PMID:Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. 1264 50

Previously, we have shown that primary afferent neurons are necessary for disease activity in immune-mediated liver injury in mice. These nerve fibers are detectable by substance P (SP) immunocytochemistry in the portal tract of rodent liver. Antagonists of the neurokinin-1 receptor (NK-1R), which is the prime receptor of SP, prevented liver damage by suppressing the synthesis of proinflammatory cytokines. Here, we investigated the influence of primary afferent nerve fibers, SP, and NK-1 receptor antagonists on hepatocyte apoptosis in vivo induced by administration of activating anti-CD95 monoclonal antibody (mAb) to mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment prevented CD95-mediated activation of caspase-3, measured as enzymatic activity in liver homogenates or by demonstration of hepatocellular immunoreactivity for active caspase-3 in liver slices, and liver damage. This effect was reversed by administration of SP to anti-CD95 mAb-treated mice depleted from primary afferent neurons. The presence of the NK-1R on mouse hepatocytes was demonstrated by immunocytochemistry and flow cytometry. Intraperitoneal pretreatment with the NK-1 receptor antagonists (2S,3S)-cis-2-(diphenylmethyl)-N-([2-methoxyphenyl]-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) or (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperadine (L-733,060) dose dependently protected mice from CD95-mediated liver injury. Similar results were obtained when apoptotic liver damage was induced by administration of tumor necrosis factor-alpha to d-galactosamine-sensitized mice. In conclusion, SP, probably by binding to its receptor on hepatocytes, might aggravate apoptotic signals in these cells. Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent liver cell apoptosis in vivo, they might be suitable drugs for treatment of immune-mediated liver disease.
 ...
PMID:Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage. 1461 92

Human mast cells are categorized into mast cells positive only for tryptase (MC(T)) and mast cells positive for both tryptase and chymase (MC(TC)). The structural appearance of tryptase-, and chymase-positive mast cells in metastatic liver disease and the variations in MC(T) and MC(TC) numbers in accordance with the origin of the primary tumors have been described in the present study. Liver mast cells are analyzed immunocytochemically using tryptase and chymase and by quantitative morphometry in 30 patients with colorectal (n = 15), gastric (n = 8), and pancreatic (n = 7) cancers and in 5 control livers. The numbers of MC(T) and MC(TC) are increased in the extratumoral liver tissue (mainly portal tracts) as compared to controls. The numbers of MC(T) and MC(TC) in and around metastases with moderate or high grade of differentiation are statistically significantly higher, as compared to those with low grades of differentiation. The numbers of MC(TC) are greater than that of MC(T) in the extratumoral liver tissue and in metastases themselves. Ultrastructurally, mast cells immunostained with tryptase and chymase have three types of granules: electron dense granules with darkly precipitated reaction product, electron lucent granules without reaction product and electron lucent granules with sparse reaction product (altered granules). Both types of mast cells have small and large in size granules, resembling the MC(TC) phenotype described earlier. Tryptase-positive mast cells have granules with discrete scrolls and particulate and beaded pattern. Chymase-positive mast cells have granules with finely granular or particulate material. Substance P (SP)- and vasointestinal polypeptide (VIP)-positive mast cells are not observed in livers with metastases. The present study suggests that liver mast cells are mainly from the MC(TC) type, and are accumulated in peritumoral and metastatic areas. They may play a role in the formation of tumor stroma, or in tumor immunology in liver metastases from various primary gastrointestinal cancers.
 ...
PMID:Structural examination of tryptase- and chymase-positive mast cells in livers, containing metastases from gastrointestinal cancers. 1466 92

Itch is a complication of liver disease. It is hypothesized that this type of itch is mediated, at least in part, by increased central opioidergic tone; a peripheral component may coexist. The role of serotonin, bile acids, substance P, and lipophosphatidic acid and the activity of the enzyme that generates it, autotoxin, has been proposed in the pathogenesis of itch. Scratching activity was significantly suppressed in association with the placebo tablet in a controlled, double-blind study; this finding supports the exploration of the placebo effect on the itch sensation and the inclusion of behavioral methodology in clinical trials in patients with this complication of liver disease.
 ...
PMID:The itch of liver disease. 2176 69