Comparative pathology of inflammation in the sheep

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h. ^,.,�:J....:) ^v ^_.-s;1Y,

PAL.Mi:.R TON 1':19JUtl, .N.Z..

'�COMPARATIVE PATHOLOGY OF INFLAMMATION IN THE SHEEP"

A thesis

p resented in partial fulfilment of the requirements for

the degree of Doctor of Philosophy at Massey University, Palmerston North

New Zealand

« ^I'

Jawahar Lal Vegad

1967

1

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Acknowledgement s

'The work rec orded in this thesis was initiat ed under the

s timulus o f Prof e ssor M.C . Lancaster , then Professor-of Animal Health in this Univer si t y . Professor Lancaster was my chi e f supervisor t h roughout th e p e riod of experim entation and was a c ont inual sourc e o f inspiration , s timulation and encouragement . I am greatly indebted to h im .

In the e arly stages o f t h e work D r W . L . K eneal y , Chief Pathologist , Palmerston North Public Hosp ital , was eo-sup erviso r and provided many h e lpful suggestions.

With Professor Lancaster's departure from New Zealand , Professor D.A . Tit chen, Professor of Physiology in thi s University b e came my

chief supervisor and he contribut e d a c onsiderable amount of exp erienc e and s timulus in the pr eparati on of the thesi s . Professor Tit chen , t o

g e ther w ith Dr W . A. G. Charlesto n , Act ing Head, Animal Heal th Department, d evoted a l arge amount of time t o cons t ructive criticism of the thesis f r om the earliest stage of it s p reparation to the f inal draft. I am g reatly indebted to them both.

In the studies involving the bio-assay of histamine, Professor F. N . Fastier and Dr J . G . Blackman ( Department of Pharmac ology and Pharmacy , O tago Medical School ) were most h elpful and generous in p ermitting me to use their fac il i ties . Dr �.M. Moriarty ( Department of Animal Heal th ) provided va�uable advice in the preparat ion of antisera�

and Mr E.J . Kirk (Department of Veterinary BiQlogy ) carried out the surgery involved in experiment s on the effect of denervat ion. I t ender my thanks t o t h em all .

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Mr D. Ward gave some t echnical assis tance with histopathologic al t e chniques and Mr J. Thompson was respons ible for managemen t ^of the animals; some of the coloured photographs and black and whi t e p rint s

were taken by Mr G.H . Burns ; Mis s M.G. Campbell and her library staff rendered i nv al uabl e assist ance t hrough ob tain ing large numbe rs o f p eriodical s which w e r e n o t h e l d in thi s University l ib rary; Mis s ^{A .} Waugh typed the thesis and made an exc el l en t job of it , and showed considerable patience at having t o typ e some passage s many times . I

am grat eful t o th em all .

The study was undert aken during the t enure of a Commonwealth Scholarship awarded by the University Gran t s Commit te e ^of New Zealand , to whom I express my s incere appr e ciati on. I would al so like to express my grati tud e t o th e Dean of Veterinary Facul t y , Professor I.J. Cunningham for his int ere s t .

Finally , I wi sh t o express my appre c iation to my wife , Nit a , who has patiently endure d my prolonged absence and has given me muc h e n couragement .

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Summary

(1) The inflammatory r esponse in the she ep has been investigated using experimental methods d eveloped in similar work on

laboratory animals.

{2) A biphas i c increase in vascular permeability occurs following turpentine and thermal injury ; an early phase seems t o be

mediated by histamine . In c ontrast, mediation o f the delayed

phase , which appears to be the maj or part of the response, remains uncertain. Histamine, a nalobulin Permeabil ity Fac tor" and p ossibly kinins , probably parti cipate. 5�Hydroxytryptamine does not appear to be a natural mediat or of inflammat ory reaction in the sheep .

(3) Histamine is readily rel eased in sheep skin , and in resp onse to a wide varie ty of stimul i .

(4) The occ urrence of the delayed phase does not depend on the o perati on of the histamine - mediated early phase .

( 5) Strophanthin-a, which interfe res with ionic transport across

cell membranes, suppresses the early h istamine phase of inflammation in the sheep .

(6) Cutaneous antigen-antibody reaction of the Arthus-type has been found to be associated with h istamine. release in the sheep.

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( 7) The effects of sodium salicylate, cortisone and indomethacin on the permeability response in the sheep are recorded . In all

cases , a significant suppression of exudate formation was obtained in the delayed phase of the permeability response following intra- pleural injection of turpent ine. These effects differ from those reported in the rat .

(8) _A factor which increases vascular permeability both by the

release of histamine and apparently through another mechanism.

has been isolated from lymph node cells of normal sheep . This is termed "lymph-node-permeability factor" .

( 9 ) Most of the increase in vasc ular permeabilit y in the inflammatory reaction in the sheep is associated with venules and comparatively lit tle with capillaries .

(10) Increased vascular permeability and emigration of leucocytes from blood vessels are dissociated phenomena.

/

(11) Permeability substances act ivated �� released by injury do not appear to exert much effect on the emigration of leucocytes.

( 12) Mast cells appeared locally more numerous in the sheep skin :following t urpen tine injury and the injection of various

permeability-increasing substances.

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(13) Histamine in doses of 100 pg attrac ted eosinoph iles to the site of injection in the sheep skin .

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Total denervation did not affect the permeability response in inflammatory reaction to turpentine inj ury in sheep skin .

(15) Toxic doses of compound 48/80 and of histamine produced sudden death in sheep . The p ost-mortem p icture has been

compared to that seen in clostridial infections in sheep , and the suggestion is made in these infe c t ions release of histamine in large or even tox i c amounts may c ontribute to the cause of death.

(16) The results obtained in the sheep suggest a closer similarity between that animal and the g uinea-pig than between sheep and rat . Certain features are c ommon t o all .

(17) The present work has revealed that there are clear differences b etween spec ies in the inflammatory mechanism . Wh ile information obtained in one species may provide some information for another , inter-spe c ies differences may be wide and basic, and it is not p ossible to extrapolate results between species . Extensive work is required to categorise the mechanisms_in domestic animals . This would p rovide a better understanding of the pathogenesis and pathology of diseases in them . It is felt that sheep may prove a useful animal in exploring certain basic p�oblems of the inflammatory reaction .

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Summary Introduction

Materials and Methods Results

...

CONTENTS

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Section 1 Studies on inflammation-

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using skin in the sheep as a test system

58

Section 2 Histamine release in cutaneous antigen

antibody reactions in the sheep

Section 3 Studies on inflammation -

using turpentine-induced pleurisy in the sheep as a test system.

Studies on the pleural exudates

using turpentine-induced pleurisy in ^the sheep as a test system.

Suppression of the increased vascular permeability by specific antagonists of chemical mediators, anti-inflammatory agents and other substances

86

- 102

depletion experiments with Compound

48/80

¹⁰⁸

Section

6

Toxicity of Compound

48/80

and histamine

in ^sheep - 111

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Section 7 Histological study of increased vascular permeability in turpentine-induced

inflammation of the skin and pleura

Section 8 Histological study of increased vascular permeability in thermal injury

Section 9 Effect of denervation on the increased vascular permeability

Section 1 0 "Lymph-node-cell permeability f actor"

Discussion

References

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1 27 130

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