PHYSIOLOGIC IMPORTANCE OF LYMPH 



I 04 I 



be discussed in detail below, there is now no question 

 but that "normal," "healthy" capillaries leak protein 

 (and other macromolecules) and that the protein 

 content of lymph collected from different areas of 

 the body is primarily an expression of the leakage of 

 these macromolecules from the blood stream. Thus, 

 during the course of a day, 50 per cent or more of 

 the total circulating protein escapes from the blood 

 stream and is returned to it via the lymphatic system. 

 An additional factor in the reluctance to the ac- 

 ceptance of the idea that lymph was primarily 

 derived from capillary filtrate was literal adherence 

 to the pore concept of capillary permeability. It was 

 difficult to reconcile the appearance of proteins and 

 other macromolecules in lymph with the size of the 

 "pores" postulated for capillary membranes (118). 

 It is now obvious that the pore concept as originally 

 reviewed by Pappenheimer (166) must be modified 

 and reconciled with the more recent work on lymph 

 to permit of the possible operation of active processes 



(141). 



Drinker and his colleagues elaborated on Starling's 

 concept of capillary permeability. As a result of 

 analysis of lymph from different areas of the body 

 they concluded "that the capillaries practically uni- 

 versally leak protein, that this protein does not 

 reenter the blood vessels unless delivered by the lym- 

 phatic system; that the filtrate from the blood capil- 

 laries to the tissue spaces contains water, salts, and 

 sugars in concentrations found in blood, together 

 with serum globulin, serum albumin, and fibrinogen 

 in low concentrations, lower probably than that of 

 tissue fluid or lymph; that water and salts are re- 

 absorbed by blood vessels and protein enters the 

 lymphatics together with water and salts in the con- 

 centrations existing in the tissue fluid at the moment 

 of lymphatic entrance" (61). During the last decade, 

 as will be discussed below, experiments particularly 

 with isotope-labeled proteins and other macromole- 

 cules have confirmed the point of view of the Drinker 

 group and have shown unequivocally that "healthy" 

 capillaries leak plasma protein and other macro- 

 molecules and that these are returned to the blood 

 stream via the lymphatics. To date, all plasma pro- 

 teins have been shown to be present in lymph from 

 all areas studied (234). 



Exlr avascular Pool and 

 Circulation of Protein 



When a labeled protein is injected intravenously, 

 the specific activity (ratio of concentrations of labeled 



and natural protein) of lymph gradually rises (44, 

 116, 149) until it reaches that of plasma in 7 to 13 

 hours in the case of the thoracic duct (220). Samples 

 of lymph and plasma analyzed after this time show 

 that the specific activities in the two compartments 

 remain equal and decline at the same slow rate. This 

 early growth type of curve suggests that protein 

 leaves the blood stream and mixes with the extra- 

 vascular protein pool before being taken up by the 

 lymph ducts. If lymph were a direct product of 

 plasma, the experiments should yield a "decay" type 

 of curve. This point of view is strengthened by experi- 

 ments in which large infusions were given to dogs 

 (116, 221). Infusions roughly equivalent to or greater 

 than plasma volume resulted in increased flow of 

 thoracic duct lymph and albumin leakage increased 

 significantly (fig. 1). It was obvious that the eventual 

 level of total circulating plasma protein was deter- 

 mined by a number of factors. Infusion results in the 

 filtration of a more dilute protein solution than that 

 filtered before the infusion, but one which has a 

 relatively greater albumin content as well as a larger 

 volume. This then mixes with the relatively more 

 concentrated preinfusion interstitial fluid so that the 

 concentration of albumin in lymph after the infusion 

 is intermediate between that of the interstitial fluid 

 formed before the infusion and the newly formed 

 interstitial fluid. The eventual effect of an infusion 

 on the total plasma protein level will thus depend 

 upon a) the degree of distention of the interstitial 

 space as a result of the infusion, since a greatly dis- 

 tended interstitial space may hold much of the protein 

 which ordinarily might have gone back to the circu- 

 lation via the lymphatics; b) the rate (and amount) 

 of albumin leaving the capillaries; c) the amount of 

 albumin present in interstitial fluid available for 

 mixing with the plasma filtrate; and d) the rate of 

 lymph flow. If the lymph does not return to the 

 venous system or if the amount disappearing from 

 the plasma is greater than the amount returning via 

 lymph, plasma albumin will be decreased and remain 

 low until the usual conditions of flow are re-estab- 

 lished. These results with isotopically labeled albumin 

 emphasize that we are not concerned with mobiliza- 

 tion of cell protein, as has been suggested in the litera- 

 ture (4, 59), but primarily with the movement of 

 interstitial fluid protein. Addition of new protein 

 from any source drained by lymph coming to the 

 thoracic duct would have been apparent by a lowering 

 of specific activity. This was never seen. 



Evidence for the existence of an extravascular 

 albumin mass as a separate entity and in equilibrium 



