SPREADING FACTORS 



323 



SPREADING FACTORS 



tain invasive bacteria such as staphy- 

 lococcus, streptococcus, pneumococcus, 

 in animal poisons such as that of rattle- 

 snakes, in secretions of insects such 

 as mosquitoes, etc. Often H. is asso- 

 ciated with other spreading factors in 

 the animal secretions. 



The in vivo effect of H. is shown by the 

 spreading reaction. In this reaction 

 any material injected in the G.S., to- 

 gether with H., spreads rapidly as if 

 ink were dropped on a blotter. The 

 reaction is best shown when a mixture 

 of any H. -containing material and any 

 colored matter is injected intradermally 

 into a rabbit. A control inoculum of 

 the colored material alone remains 

 largely localized where the presence of 

 the injection has left it. 



H. was identified to a mucolytic en- 

 zyme in 1939. The action of the en- 

 zyme, or rather of the group of enzymes, 

 has been and still is subject to extensive 

 biochemical study into which we cannot 

 enter. Essentially, H.A. attacked by 

 the specific enzyme contained, for in- 

 stance, in a simple rabbit testicle ex- 

 tract, is first depolymerized and then 

 split into its components, glucuronic 

 acid and acetyl glucosamine. The 

 first effect manifests itself by a sudden 

 drop in the viscosity of the solution 

 containing the polysaccharide, for in- 

 stance, a simple extract of umbilical 

 cord. 



This reaction in the test tube is the 

 counterpart of the spreading reaction 

 in the animal. In the latter case, there- 

 fore, the H.A. of the ground substance 

 is similarly attacked by the injected 

 H. and the jelly is quickly liquefied. 

 What used to be a barrier is now a 

 pathway, and consequently, any mate- 

 rial injected together with the enzyme 

 will easily spread throughout the inter- 

 cellular atmosphere. Mechanical pres- 

 sure increases the diffusion consider- 

 ably. 



The spreading reaction also takes 

 place, although far less conspicuously 

 than in the skin, in tissues in which con- 

 nective tissue exists in formations sus- 

 ceptible of being injected. Whether H. 

 attacks components of the blood capil- 

 laries resulting in increased capillary 

 permeability is still a debatable point. 

 At any rate, the permeability of the 

 blood capillaries is considerably in- 

 creased by some factor which is regu- 

 larly present in the materials contain- 

 ing H. 



There are other S.F. which act on the 

 G.S. of the mesenchyme, but their 

 mode of action is far less known than 

 in the case of H. The effect of azopro- 

 teins and ascorbic acid seems to be of 



only a physical, depolymerizing nature. 

 Others, found in several tissue extracts, 

 bacterial cultures and animal secre- 

 tions, and also simple chemicals, do 

 not affect H.A. in vitro, and their 

 spreading effect may largely be due to 

 edema formation, as shown by the lack 

 of spreading in the skin of the dead 

 rabbit. It may be quite important 

 that, as shown recently, derivations of 

 H.A. have a spreading effect even in 

 the dead rabbit. All these facts em- 

 phasize the complexity of the spreading 

 reaction, and suggest that more atten- 

 tion should be paid to S.F. other than 

 H. Such study could prove to be ex- 

 tremely fruitful. 



With the above reviewed as a back- 

 ground, we are on a solid basis to 

 explain phenomena of fundamental 

 importance in pathology, such as the in- 

 vasion of the lung by the pneumococ- 

 cus; the progressive march of erj^sip- 

 elas; the brutal invasion of tissues 

 following snake bite; the efficacy in 

 the inoculation of infectious agents 

 carried by insect vectors; and so many 

 others. 



In the domain of physiology, besides 

 other possible effects we can under- 

 stand the liberation of the ovum from 

 its surrounding granulosa cells as an 

 event preceding fertilization. H.A. 

 is largely present in the cement holding 

 these cells together, and from the at- 

 tack of the acid by the enzyme secreted 

 by the spermatozoa, this cement is 

 liquefied and the granulosa cells be- 

 come dispersed. 



In the field of pharmacology, we can 

 also understand the powerful enhance- 

 ment of the effect of therapeutic agents 

 such as the various solutions adminis- 

 tered in clysis, of local anesthetics, of 

 antibiotics, etc. when the agent is in- 

 jected together with H. which will pro- 

 mote its rapid spreading and absorp- 

 tion. Also, the injection of H. in 

 edematous areas subsequent to injury 

 greatly accelerates the absorption of 

 the extravasated fluid, possibly the 

 effect of the enzyme being here of a 

 more complex nature. 



If a dye solution is injected intra- 

 dermally into animals it will sometimes 

 diffuse (although far less than if H. 

 is added) depending on different fac- 

 tors such as age, sex, genetic constitu- 

 tion, etc. of the host. This simple 

 experiment indicates that the G.S. has a 

 physiological permeability or tonus, 

 subject to changes. When the per- 

 meability is decreased the effect is 

 manifest by a suppression of the spread- 

 ing effect of H., the opposite being prob- 



