Putative Roles of Bradykinin and the Kinin System in Pancreatitis

Griesbacher, Thomas; Lembeck, Fred

doi:10.1016/b978-012249340-9/50014-0

Cited by 6 publications

(10 citation statements)

References 132 publications

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“…The high pancreatic and gastrointestinal tract expression of several KLK genes may also prove to be of significance since tissue kallikrein has already been shown to play a role in the (patho)physiology of these tissues (2,49). In summary, we have physically mapped the KLK locus, providing a definitive fine map of this region at 19q13.4 and have further clarified the size and expression patterns of the extended human KLK gene family.…”

Section: Discussionmentioning

confidence: 96%

Tissue-specific Expression Patterns and Fine Mapping of the Human Kallikrein (KLK) Locus on Proximal 19q13.4

Harvey¹,

Hooper²,

Myers³

et al. 2000

Journal of Biological Chemistry

139

100

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The tissue or glandular kallikreins (KLK) are members of a highly conserved multigene family encoding serine proteases that are central to many biological processes. The rodent KLK families are large, highly conserved and clustered at one locus. The human KLK gene family is clustered on chromosome 19q13.3-13.4, and until recently consisted of just three members. However, recent studies have identified up to 11 new members of the KLK family that are less conserved than their rodent counterparts. Using a Southern blot and sequence analysis of 10 BACs and cosmids spanning approximately 400 kilobases (kb) either side of the original KLK 60-kb locus, we demonstrated that these genes also lie adjacent to this. We have also clarified the position of several microsatellite markers in relation to the extended KLK locus. Moreover, from Southern blot analysis of the cosmids and BACs with a degenerate oligonucleotide probe to the histidine-encoding region of serine proteases, we have shown that there are no other serine protease genes approximately 400 kb centromeric and 220 kb telomeric of the extended locus. We performed an extensive analysis of the expression patterns of these genes by poly(A) ؉ RNA dot blot and reverse transcriptase-polymerase chain reaction analysis, and demonstrated a diverse pattern of expression. Of interest are clusters of genes with high prostate (KLK2-4) and pancreatic (KLK6 -13) expression suggesting evolutionary conservation of elements conferring tissue specificity. From these findings, it is likely that the human KLK gene family consists of just 14 clustered genes within 300 kb and thus is of a comparable size to the rodent families (13-24 genes within 310 and 480 kb, respectively). In contrast to the rodent families, the newest members of the human KLK family are much less conserved in sequence (23-44% at the protein level) and appear to consist of at least four subfamilies. In addition, like the rat, these genes are expressed at varying levels in a diverse range of tissues although they exhibit quite distinct patterns of expression.

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Section: Discussionmentioning

confidence: 96%

Tissue-specific Expression Patterns and Fine Mapping of the Human Kallikrein (KLK) Locus on Proximal 19q13.4

Harvey¹,

Hooper²,

Myers³

et al. 2000

Journal of Biological Chemistry

139

100

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“…Kallikrein-like activity could also be determined in the blood and ascitic fluid. Conflicting data were, however, obtained as to the relative importance of glandular vs. plasma kallikrein with respect to kinin release and/or the development of haemodynamic symptoms [3].…”

Section: Experimental Evidence For the Involvement Of The Kks In Pancmentioning

confidence: 99%

“…Measurements of capillary blood flow are frequently based on morphological methods and therefore have resulted in reports of increased capillary perfusion as well as reduced numbers of capillaries [3]. Since impairment of pancreatic microcirculation is assumed to play an important role in the progression of oedematous to necrotizing pancreatitis, further insight into the changes in blood flow induced by the experimental models and the possible involvement of kinins is clearly desirable.…”

Section: Effects Of Bradykinin B 2 Antagonistsmentioning

confidence: 99%

“…Much more development has taken place in the field of B 2 receptor antagonists [13]. Current B 2 antago-Griesbacher nists of peptide nature such as icatibant (Hoe-140; D-Arg-[Hyp 3 , Thi 5 , D-Tic 7 , Oic 8 ]-bradykinin) have a considerable duration of action in vivo. However, these might be replaced in future by nonpeptide antagonists with oral activity such as FR173657 [14].…”

Section: Drugs Affecting the Activity Of The Kksmentioning

confidence: 99%

“…A more detailed review on the putative roles of kinins in the pancreas has recently been published [3]. Studies relevant to the possible role of kinins in acute pancreatitis that have been published since then are included in the present paper.…”

Section: Introductionmentioning

confidence: 99%

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Kallikrein-Kinin System in Acute Pancreatitis: Potential of B<sub>2</sub>-Bradykinin Antagonists and Kallikrein Inhibitors

Griesbacher

2000

Pharmacology

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The development of selective antagonists for bradykinin B₂ receptors has greatly advanced research on the role of the kallikrein-kinin system in acute pancreatitis. Kinins released during the course of the inflammatory injury are the major cause of the vascular symptoms, i.e. pancreatic oedema formation and its consequences, such as haemoconcentration, hypovolaemia and hypotension. Kinins are also involved in the accumulation of potentially cytotoxic factors in the pancreatic tissue. However, treatment with B₂ antagonists must begin prior to the formation of pancreatic oedema in order to inhibit or attenuate the vascular effects. Visceral pain as a possible target symptom for treatment with B₂ antagonists at later time points is suggested by the B₂ receptor-mediated activation of nociceptive afferents.

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