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Inhibited permeability responses to intradermally injected histamine, serotonin and bradykinin were observed in leucopenic rats, when compared to those measured in normal animals. Significant reversal of the inhibited responses was seen when leucopenic rats were given suspensions of lymphocytes i.v. Suspensions of PMN granulocytes, however, were ineffective. In both cases, the volumes of the suspensions contained adequate quantities of the particular cells to counteract their deficiency. Histological changes provoked by carrageenin in the paws of leucopenic rats injected with suspensions of lymphocytes resembled those of normal rats, the main difference being that the number of cells which had emigrated into the affected tissues was reduced. In leucopenic controls or leucopenic animals injected with suspensions of PMN granulocytes, minimal histological alterations were observed. It is concluded that lymphocytes play a role in the development of acute inflammatory reactions.

The participation of sensory nervous structures in the development of inflammatory responses in the rat's paw was investigated. Electrical antidromic stimulation of the saphenous or sciatic nerves during 20 min produced an oedematous response in the paw and potentiated the reaction to locally injected carrageenin. On the other hand, decreased responses to carrageenin were observed either when the sciatic nerve was sectioned 15 days before or when a prolonged electrical stimulation (45 min) of the nerve preceded by 1 h the injection of the irritant into the paw. However, if the sciatic nerve was sectioned 30 days before, the inflammatory response to carrageenin in this paw was equivalent to that observed in the contralateral, intact paw. It is suggested that sensory nervous structures might contribute to the development of inflammatory responses, through the release of an active agent, probably from neural origin. This agent would be depleted by prolonged stimulation of sensory nerves. Following partial denervation, the remaining sensory nervous structures in the affected area might develop compensatory mechanisms to influence the institution of the reaction.

Leucopenia rendered rats unresponsive to various inflammatory stimuli. The intensity of the inflammatory response in such animals was restored by i.v. administration of suspensions of lymphocytes, but not of granulocytes. This restorative effect was blocked by both steroidal and non-steroidal anti-inflammatory drugs. Utilizing carrageenin to induce inflammatory responses in the rat's paw, the effect of these drugs on lymphocytes was observed in two circumstances. First, following incubation of the cells with the drugs in concentrations not exceeding the peak plasma levels estimated for these substances in man or laboratory animals; the effect of the drugs seemed selective, since anti-histamine and anti-serotonin agents, as well as amethopterin, were devoid of action. Second, when lymphocytes were collected from rats previously treated with the various anti-inflammatory agents, injected 6-hourly during periods of 18 and 36 h, respectively, for steroidal and non-steroidal anti-inflammatory substances. The total amounts given were lower than those required to produce consistent anti-inflammatory effects in normal animals, when the drug was given as a single dose before injection of the irritant. It is concluded that the pro-inflammatory function of lymphocytes in non-immune inflammation can be blocked by steroidal and non-steroidal anti-inflammatory agents.

Light and electron microscopic studies showed that blood vessels of the cremaster muscle of alloxan-diabetic rats under the local influence of histamine or serotonin presented less labelling by colloidal carbon, previously injected i.v., than vessels of normal rats. The hyporeactive state of these vessels was promptly reversed to normal conditions by the administration of insulin. Insulin also potentiated leakage of carbon particles in the vessels of normal animals. These findings add new evidence that insulin might be involved in vascular events following injury and that decreased levels of the hormone, as occurring in diabetes, might result in decreased inflammatory reactions.

Rats selectively depleted of lymphocytes by chronic drainage from the thoracic duct during a 3-day period presented a marked lymphopenia, and decreased responses to carrageenin injected into one of the hind paws. The intensity of the inflammatory responses in thse animals was restored by the i.v. administration of suspensions of viable or lysed lymphocytes, collected from the spleen or lymph of normal animals. A spontaneous reversal of the depressed responses to carrageenin was observed 40 days after the period of lymph drainage, when lymphocyte counts were again normal in blood. If highly inbred rats were used, the i.v. injection of syngeneic lymphoid cells was equally effective in restoring the inhibityed inflammatory responses resulting from lymphocyte depletion. Artificial obstruction of the thoracic duct, with interruption of lymphocyte recirculation, was followed by decreased lymphocyte counts in blood and severely depressed inflammatory responses to carrageenin. This unresponsive state was corrected as the animals recuperated, probably coincidentally with the development of collateral lymph channels and as the temporarily disturbed blood picture returned to normal. It is concluded that lymphocytes can participate in the development of non-immune inflammation through the release of pro-inflammatory factors. This release is independent of previous sensitization of the cells.

The vascular permeability response induced in the rat by intracutaneous histamine or serotonin is noticeably influenced by previous adrenalectomy or treatment with corticosterone. Permeability responses were demonstrated by the local exudation of circulating Evans blue at sites of intracutaneous injection of the above permeability factors, the intensity of the responses being assessed by the diameter of the blue lesions as well as by the amount of exuded dye. In adrenalectomized rats maintained for 72-80 h on 0-9% solution of NaCl, the permeability response to histamine was enhanced about 10-fold, that to serotonin about 5-fold. When rats were given subcutaneous corticosterone, 1-0 mg/animal 1 h before testing, the responses to the same 2 permeability factors were decreased about 10-fold and 5-fold respectively. Corticosterone also decreased the enhanced responses in adrenalectomized rats to levels somewhat below those in mock adrenalectomized controls. The results support the proposal from other work that vascular exudation in experimental inflammation is regulated by an anti-inflammatory factor that accumulates in injured tissues and owes its effect to release of corticosteroids.

Drug-induced leucopenia renders rats hyporeactive to various inflammatory stimuli. Administration to leucopenic rats of suspensions of lymphocytes, sufficient to apparently correct the induced lymphocytopenia, led to a partial but marked reversal of the inhibited responses. Similar results were observed when lysates of lymphocytes or filtrates of the disintegrated cells were injected. Suspensions of polymorphonuclear granulocytes, on the contrary, were ineffective in producing a reversal of inhibited inflammatory reactions in leucopenic rats. The presence of a proinflammatory factor (LpIF) in lymphocytes, which might be involved in the modulation of acute inflammatory responses is suggested.

Leucopenic rats were injected i.v. with either allogeneic or syngeneic lymphocyte suspensions and their capacity to respond to carrageenin tested at various intervals after the injection of the cells. The carrageenin-induced inflammatory response, which is characteristically attenuated in leucopenic animals, was partially but none the less definitely restored when allogeneic cells were transfused 20 min before the irritant, and less so when they were given 1 or 2 h before. Syngeneic cells were effective in restoring this response up to 2 h after injection. Only a small fraction of the exogenous cells, either allogeneic or syngeneic, remained in the blood, and this for short intervals. One hour after administration of cell suspensions blood leucocyte counts again attained previous values. The same rate of disappearance of the cells from blood was observed in splenectomized rats. Removal of the cells from circulation was thought to reflect "homing" into lymphoid tissues and other tissues, but not selectively in the spleen. Lymphocyte constituents, obtained by cell disintegration and injected i.v. into leucopenic rats, did not cause any change in blood leucocyte counts and yet restored the previously inhibited inflammatory response to carrageenin, as much as the viable cells. It is suggested that inflammation-producing materials, either deposited in tissues or formed or transformed at a site of injury, might gain access to the lymphatics during the early stages of a non-immune, inflammatory response, and "stimulate" lymphoid cells in adjacent lymphoid tissues either to release pro-inflammatory factors or to migrate to the site of injury, where they would exert pro-inflammatory activities. Apparently, only a small number of these cells in involved in the response.

Rats were subjected to various experimental procedures which affected lymphocyte numbers, in an attempt to investigate the participation of individual subpopulations of these cells in the development of acute, non-immune inflammation. Deficient T function, as evidenced in neonatally thymectomized animals, or in 6-week-old animals thymectomized and afterwards exposed to multiple total-body X-ray irradiations, did not interfere with the development of the acute inflammatory responses of the animals to carrageenin. In the former circumstance, the numbers of circulating B lymphocytes, identified by the presence of surface immunoglobulins, were increased. In thymectomized and irradiated rats, the B-lymphocyte subpopulation was reduced. Circumstances causing attenuated inflammatory reactions to carrageenin resulted, first, from lymphocyte depletion by chronic drainage from the thoracic duct and, second, from irradiation of the animals with a single large dose of X-ray, the animals being tested 24 h after irradiation. B lymphocytes in blood remained within the normal range after chronic lymphatic drainage, but a large dose of X-ray markedly reduced their number. In both cases the attenuation of the responses to carrageenin did not seem to be associated with nonspecific hyporeactivity, or with the effect of the treatments on the other blood cells, It is suggested that the development of acute, non-immune inflammation is influenced by lymphoid cells which might constitute a specific subclass of cells, distinct from fully differentiated T and B lymphocytes.