The time-response and magnitude of HCG-induced vascular changes are different in scrotal and abdominal testes

Adult unilaterally cryptorchid rats were injected with 50 IU human chorionic gonadotrophin (hCG). At 4, 8, 24 and 72 h after treatment, testicular vascular permeability was studied by injecting colloidal carbon intravenously. The number of blood vessel profiles labelled with carbon was increased by hCG in both types of testes, but the response was more sustained in abdominal than in scrotal testes. The number of polymorphonuclear leucocytes (PMNs) accumulating in testicular blood vessels and migrating into the interstitial space in response to hCG treatment was also measured. The volume density of intravascular and interstitial PMNs was increased in both types of testes but the peak response was larger in scrotal than in abdominal testes. PMN accumulation and vascular leakage were apparently correlated in the scrotal but not in the abdominal testes.
Testicular interstitial fluid (IF) was collected from intact and unilaterally cryptorchid adult rats. The IF was diluted with sterile buffer and injected intracutaneously in test animals. The vascular permeability response was assessed by measuring the leakage of Evans blue into the injection sites. IF from scrotal and abdominal testes increased vascular permeability in the skin. The response was rapid and transient. IF collected from rats given hCG 24 h earlier did not increase vascular permeability. The vascular permeability response to IF was reduced slightly in neutrophil-depleted animals. The inflammation mediator present in IF cannot explain the kinetics and magnitude of the hCG-induced changes in vascular premeability in intact or unilaterally cryptorchid rats.     

Effects of repeated injections of human chorionic gonadotrophin on vascular permeability, extracellular fluid volume and the flow of lymph in the testes of rats

Testicular lymph flow, interstitial fluid volume and vascular permeability have been measured in adult male rats injected subcutaneously with hCG daily for up to 4 consecutive days. Albumin clearance was also measured in rats given two or three hCG injections at 2- or 3-day intervals, or every 2 days for 22 days. While a single dose of hCG increased vascular permeability and lymph flow within 24 h, subsequent daily injections did not produce any additional response and, in fact, values returned towards control levels. A second hCG dose 2 days after an initial dose did produce another similar increase in the clearance of albumin injected directly into the testis and, with continued injections every second day, a response was still evident after 22 days. The response to the second dose of hCG occurred at a time when down-regulation of hCG receptors on Leydig cells is reported to be maximal. These results suggest that in the testis, the vascular response to hCG does not require the normal number of luteinizing hormone (LH) receptors, although other evidence suggests that Leydig cells must somehow be involved.     

Effect of unilateral cryptorchidism on the intertubular tissue of the adult rat testis: evidence for intracellular changes within the Leydig cells

Adult male rats were made unilaterally cryptorchid for 1, 2 or 4 weeks, and the morphological response of the Leydig cells was then studied using morphometric assessment of total Leydig cell volume and number per testis in abdominal and scrotal testes. Serum hormone levels were measured and the steroidogenic properties of isolated Leydig cells were evaluated by in-vitro stimulation with hCG and interstitial fluid (IF) obtained from normal rat testes. Total Leydig cell volume and number per testis were not altered in abdominal vs scrotal testes, although the volume of the abdominal testis was 46, 29 and 21%, respectively, of the volume of the contralateral scrotal testis after 1, 2 and 4 weeks. This reduction was accompanied by significant (P less than 0.05) elevation of the serum levels of FSH and LH, although serum testosterone levels were unchanged from the normal range. Despite the lack of quantitative alterations in Leydig cell morphology, hCG- and IF-stimulated testosterone production was significantly (P less than 0.01) greater by abdominal Leydig cells when compared with scrotal Leydig cells derived from the same animals. Ultrastructural examination of Leydig cells in situ suggested an increase in volumetric density of mitochondria in abdominal Leydig cells. Together with the enhanced steroidogenic responses of these cells, these findings suggest that disruption of spermatogenesis in the cryptorchid testis is accompanied by intracellular activation of Leydig cells. Since these effects were not exhibited by Leydig cells from the scrotal testis it is concluded that local factors within the cryptorchid testis are responsible, at least in part, for regulation of Leydig cell activity.     

Interaction of hCG with testicular interstitial fluid produces a leucotactic factor

An intratesticular injection of hCG (5 ng) mixed with testicular interstitial fluid (IF) increases vascular permeability in the rat testis. The present results show that the permeability increase induced by this treatment is accompanied by a massive accumulation of polymorphonuclear leucocytes (PMNs) in both the testicular postcapillary venules and the interstitium. Depletion of neutrophils in the circulation by treatment with anti-neutrophil serum significantly inhibited the permeability increase induced by this treatment. An intratesticular injection of PMNs (10(7) cells) or hCG alone had no effect on permeability, but a combination of the two caused a significant increase in permeability. The PMNs were found to secrete a component in vitro which, when injected intratesticularly together with hCG, caused a increase and a simultaneous massive accumulation of PMNs in the postcapillary venules and interstitium. This permeability increase was prevented by the serine protease inhibitor p-aminobenzamidine, suggesting an involvement of the plasminogen activator system in the response. The results suggest that hCG interacts with an IF component to produce leucotactic factors that increase permeability indirectly by attracting PMNs to the tissue, and that the IF component may originate in the PMNs.     

Differential actions of gonadotropin-releasing hormone and human chorionic gonadotropin on interstitial fluid volume and immunoglobulin G concentrations in adult rat testis

Gonadotropin-releasing hormone (GnRH) agonists regulate testicular interstitial fluid (tIF) volume, most probably via specific receptors on Leydig cells. The aim of this study was to confirm the interaction between GnRH and Leydig cells in regulation of testicular fluid, and to examine the effects on serum proteins in testis. Unilateral intratesticular injection of a GnRH agonist (100 ng/testis) caused a 50% reduction in tIF volume within 2 hours. Destruction of Leydig cells by treatment with ethane dimethane sulfonate also caused a similar decline in tIF volume; however, GnRH agonist treatment had no additional influence on this response in Leydig cell-depleted testes. GnRH agonist treatment had no effect on serum protein permeability in testis as indicated by maintenance of the tIF/serum immunoglobulin G (IgG) concentration gradient. Injection of human chorionic gonadotropin (hCG, 100 IU) had no effect on tIF volume at 2 hours, but increased the permeability of the testicular vasculature to serum IgG. At 20 hours after hCG injection, tIF volume was increased twofold, while the testicular permeability barrier to IgG appeared to have been restored. These data indicate that the acute inhibitory action of GnRH on vascular fluid permeability is dependent upon Leydig cells, confirming that these cells are the primary site of GnRH action on testicular vasculature. The data also indicate that supraphysiological doses of hCG cause a rapid increase in testicular permeability to serum proteins, which occurs prior to the well-characterized stimulation of tIF volume. These data provide further evidence that the concentration of serum proteins in tIF and the volume of tIF are both under regulatory control involving Leydig cells, but are independently regulated.     

Treatment with an LHRH agonist or hCG increases interstitial fluid volume and permeability to Evans blue in the mouse testis

Treatment of adult mice with 1 microgram of an LHRH-agonist or with 5 i.u. hCG, subcutaneously, resulted in an increase in the permeability to intravenously injected Evans blue into the testicular interstitial space and in the volume of testicular interstitial fluid. These changes are probably related to an increase in vascular permeability but, in contrast to the situation in rats, this was accompanied neither by an accumulation of polymorphonuclear leucocytes in testicular blood vessels nor by the formation of large inter-endothelial cell gaps in postcapillary venules. The mechanisms mediating the gonadotrophin-induced increase in vascular permeability in the mouse testis thus remain unknown.     

Vascular permeability effect of adenovirus-mediated vascular endothelial growth factor gene transfer to the rabbit and rat skeletal muscle.

OBJECTIVE: Vascular endothelial growth factor has been used in preclinical studies and phase 1 and 2 clinical trials as a potent mediator of therapeutic angiogenesis; however, its ability to enhance the vascular permeability may be a source of potential complications. The objective of this work was to evaluate the effects of the intramuscular injection of an adenovirus vector coding for the 121-amino acid form of vascular endothelial growth factor (Ad.VEGF(121 )) on vascular permeability and edema development in rabbits and rats. METHODS: Different concentrations of Ad.VEGF(121 ) ranging from 10(5) to 10(10) plaque-forming units/mL (3 x 10(6)-3 x 10(11) particles/mL) were injected into hind limb or forelimb muscles of Wistar rats or rabbits. The size of the scrotum, the circumferences of limbs, and the concentration of vascular endothelial growth factor in the serum were measured daily after injection. RESULTS: The injection of different concentrations of Ad.VEGF(121 ) into the hind limb muscles of rabbits led to a dose-dependent scrotal edema in rabbits at concentrations higher than 10(7) plaque-forming units/mL (P =.002). The edema developed slowly, reached its maximum level 6 days after the injection, and spontaneously resolved thereafter. At concentrations higher than 10(9) plaque-forming units/mL the scrotal edema was accompanied by skin necrosis (P =.0001). No scrotal edema was observed in rats. CONCLUSIONS: The massive species-specific scrotal edema accompanied by skin ulceration and necrosis was observed only in rabbits treated with Ad.VEGF(121 ) in concentrations exceeding therapeutic doses. The therapeutic doses of Ad.VEGF(121 ) resulted in only moderate transient scrotal edema in rabbits, suggesting that the potential for side effects of vascular endothelial growth factor therapy as a result of increased vascular permeability should not be very alarming for generally healthy patients and may not cause a significant clinical problem in the treatment of peripheral vascular diseases.     

Impaired estrogen production by Leydig cells of the naturally retained testis in unilaterally cryptorchid boars and stallions

Estrogen production in vitro was compared for Leydig cells from cryptorchid and scrotal testes in boars and stallions. Animals with natural and experimental cryptorchidism were used. Purified Leydig cells were prepared from testes of mature animals by collagenase treatment and Percoll density gradients. After incubation for 3 hours (1 X 10(6) cells), estrone sulfate and estrone in the media were measured by direct radioimmunoassay. Androstenedione and testosterone in media extracts also were determined. Cells from the abdominal testis of unilateral cryptorchid boars and stallions showed impaired estrogen production compared with that of the contralateral scrotal testis. Surgical translocation of the scrotal testis to the abdominal cavity in four unilaterally cryptorchid, prepubertal boars did not result in a reduced capacity for estrogen secretion by Leydig cells examined after puberty. Cells from the naturally retained testis in each of these four animals produced practically no estrogen. In a naturally bilateral cryptorchid stallion, there was a high rate of estrogen secretion by both testes. It was concluded that the scrotal testis of a unilaterally cryptorchid animal exerts a suppressive influence on estrogen formation by the abdominal testis.     

Early signs of Sertoli and Leydig cell dysfunction in the abdominal testes of immature unilaterally cryptorchid rats

Testicular descent was prevented unilaterally by cutting the gubernaculum testis of newborn rats. When 20 days old unilaterally cryptorchid rats were injected intraperitoneally with 2 μg bFSH per gram body weight and killed 6 h later when testicular testosterone (T) and oestradiol (E₂) concentrations were determined. The increase in E₂ was subnormal in abdominal testes. In 18-day-old unilaterally cryptorchid rats the efferent ducts were ligated bilaterally, and the rats were killed 48 h later. The weight increase, due to accumulation of seminiferous tubule fluid, was significantly greater in the abdominal testes. In contrast, the ABP content of the abdominal epididymis was subnormal in 20-day-old unilaterally cryptorchid rats. Unilateral orchidectomy was performed in 16-day-old unilaterally cryptorchid rats and at 20 days of age intratesticular T and E₂, and plasma FSH and LH concentrations were determined and compared to that in 20-day-old control unilaterally cryptorchid rats. Removal of an abdominal testis resulted in increased plasma FSH and intratesticular E₂, whereas plasma levels of LH and intratesticular levels of T were unaffected. Removal of a scrotal testis resulted in increased plasma FSH and LH coupled with increased intratesticular T and E₂. Rats with a single abdominal testis had higher plasma FSH and LH and intratesticular T, but similar intratesticular E₂, than rats with a single scrotal testis. It is concluded that Sertoli and Leydig cell function are influenced by cryptorchidism at a stage when the temperature difference, and the morphological differences between the testes are very discrete.     

Surveillance following orchidectomy for Stage I testicular cancer

Surveillance following orchidectomy was introduced in the management of Stage I testicular nonseminoma in 1979 and Stage I seminoma in 1983. Of 132 nonseminoma patients followed for 12-84 months (median 43 months) the relapse rate is 27%. Relapses were diagnosed 2-44 months after orchidectomy with 90% of relapses appearing within the first year. Of the 132 patients, 131 are alive and disease-free. The pattern of relapse was as follows: 47% of relapses occurred in abdominal nodes, 13% in abdominal nodes and lung, 17% in the lung and 23% with elevated serum markers as the only evidence of disease; 26% of relapsing patients had normal serum AFP and hCG levels. The prognostic significance of thirteen clinical histopathological and biochemical factors has been analysed by multiple regression analysis. Histology and lymphatic invasion within the primary tumour are significant independent prognostic factors. A total of thirty-six patients had scrotal interference prior to removal of the primary tumour. This was not a contra-indication to surveillance. None has developed scrotal recurrence and the overall relapse rate (11%) is comparable to that observed in the surveillance series as a whole. Fifty-two patients with Stage I seminoma have been observed from 12-41 months after orchidectomy. Seven (13%) have relapsed and six of the seven relapses have been confined to retroperitoneal lymph nodes. Preliminary data suggests that pre-orchidectomy elevation of serum hCG is not a significant prognostic factor.     

Lung injury and lung lysosomal enzyme release during endotoxemia

We measured the release of the lysosomal enzymes β-glucuronidase and aryl sulfatase A into lung lymph and plasma after Escherichia coli endotoxin and compared these changes with the pulmonary vascular injury produced. We used 18 unanesthetized sheep, infusing doses of endotoxin from 1 to 10 αg/kg. We identified an early injury phase characterized by severe pulmonary hypertension, a three- to fivefold increase in protein-poor lung lymph flow, and a marked decrease in blood leukocyte count. This was followed several hours later by an increase in vascular permeability with a three- to fivefold increase in protein-rich lung lymph. Lymph lysosomal enzymes increased 200–800% over baseline with a sharp increase occuring during the early hypertension phase. Lymph β-glucuronidase correlated well with the change in vascular permeability measured by lymph flow, r = 0.7. Plasma enzyme values increased, but to a much lesser degree, correlating poorly, r = 0.2, with the lung injury. However, increases over baseline greater than 200% corresponded into with later systemic shock and mortality. We conclude that lysosomal enzymes are released into the lung after endotoxin, probably from sequestered leukocytes, with the degree of release corresponding to the degree of vascular injury.     

Age-related differences in testicular microcirculation

Different aspects of testicular microcirculation were studied in rats aged 20, 24 or 90 days, in order to determine if maturational changes in the testis could influence its vasculature. Using laser Doppler flowmetry, it was found that vasomotion was not present in 20-day-old rats, but it could be induced by hCG-treatment given 32 h prior to flow measurements. In rats aged 24 days vasomotion was present in the testis but it was not influenced by hCG treatment, in contrast to adult rats in which testicular vasomotion disappeared after hCG treatment. In all age-groups, hCG treatment induced an increase in testicular interstitial fluid (IF) volume, which was most pronounced in young rats. In young rats, as in adults, there was an increase in the volume density of polymorphonuclear (PMN) leucocytes in testicular blood vessels after hCG treatment. However, rats aged 20 or 24 days did not exhibit any significant extravascular migration of leucocytes as occurred in adult rat testis after hCG injection. The deposition of colloidal carbon particles observed in adult rats after hCG-treatment was also not seen in young rats. It is concluded that the vasculature of the immature rat testis responds to hCG stimulation with an increase in IF volume. However, when compared to adult rats, different mechanisms may be operating because no evidence for opening of inter-endothelial cell gaps was observed in the testis of young rats.     

A thromboxane analog increases pulmonary capillary pressure but not permeability in the perfused rabbit lung

Thromboxane has been implicated as a mediator of pulmonary hypertension and pulmonary edema in acute respiratory failure. Pulmonary edema may result from increased pulmonary capillary hydrostatic pressure or from increased pulmonary vascular permeability. We therefore studied the effects of a stable thromboxane analog, U46619, on these two parameters in the perfused rabbit lung. Pulmonary capillary pressure was measured by the double vascular occlusion method, and pulmonary vascular permeability was estimated by measurement of the pulmonary fluid filtration coefficient (Kf). U46619 infusion produced pulmonary hypertension and lung weight gain; increased both the arterial (precapillary) and venous (postcapillary) components of pulmonary vascular resistance; and increased pulmonary capillary pressure from 4.7 +/- 0.5 to 9.0 +/- 0.7 mmHg (P less than 0.01). The isogravimetric pressure (equivalent to the capillary pressure corresponding to no lung weight gain) was 4.0 +/- 0.4 mmHg before U46619 and 4.6 +/- 0.4 mmHg during U46619. Therefore, U46619 significantly increased capillary pressure above isogravimetric pressure and resulted in the development of pulmonary edema. U46619 did not affect vascular permeability as measured by Kf. We conclude that pulmonary venoconstriction resulting in increased pulmonary capillary hydrostatic pressure is the major mechanism by which thromboxane produces pulmonary edema in isolated lungs.     

Wood smoke inhalation increases pulmonary microvascular permeability

The effect of wood smoke inhalation (SI) on pulmonary vascular permeability was studied in open-chested, anesthetized dogs. Animals were divided into two groups. A prenodal lymphatic vessel was cannulated in group I (n = 7), and baseline (BL) lung lymph flow (QL) and lymph (CL) and plasma (CP) protein concentrations were measured. The animals' lungs were then ventilated with wood smoke for 5 minutes. Left atrial pressure (Pla) was increased above baseline (mean 16.7 +/- 2.2 mm Hg), and the ratio of CL to CP was used to assess endothelial permeability at high lymph flows. There was little change in either QL (BL: 27 +/- 9; SI: 27 +/- 5 microliters/min) or CL/CP (BL: 0.76 +/- 0.03; SI: 0.74 +/- 0.02) after SI at normal Pla. Elevation of Pla caused a significant increase in QL (136 +/- 15 microliters/min), but CL/CP (0.67 +/- 0.02) failed to decrease significantly at high lymph flows. In group II (n = 15) total protein concentration of airway fluid was compared with that of plasma after smoke inhalation, intravenous alloxan, and increased Pla. The ratio of protein concentration in airway fluid to plasma after SI (0.70 +/- 0.07) was greater than that obtained with increased Pla (0.64 +/- 0.07) but less than that after alloxan (0.85 +/- 0.04). These data indicate that SI in the dog results in a moderate increase in pulmonary vascular permeability that is less severe than that induced by alloxan.     

Effect of OKY 046, a thromboxane synthase inhibitor, on lung vascular permeability after pulmonary embolism in sheep.

OKY 046, a specific thromboxane synthase inhibitor, was used to investigate whether large pulmonary emboli, like microemboli, cause an increase in thromboxane A2 and an associated increase in vascular permeability in sheep. Nineteen sheep were anaesthetised and had cannulas inserted into the afferent lymphatic of the caudal mediastinal lymph node and pulmonary and carotid arteries. Several days later the animals were pretreated with placebo or OKY 046 0.4 mg/kg one hour before being given clotted blood 0.5 g/kg intravenously. After embolisation in the control animals mean pulmonary artery pressure (MPAP) rose from 12 to 34 mm Hg and pulmonary artery wedge pressure (PAWP) fell from 4.4 to 1.5 mm Hg; the cardiac index did not change but the physiological shunt (QS/QT) rose from 17% to 50%. One hour after embolisation the platelet count fell from 76 to 32 x 10(6)/l whereas at 15 minutes thromboxane B2 rose from 116 to 560 pg/ml in plasma and from 324 to 795 pg/ml in lymph (p less than 0.05). By 2 hours the concentration of thromboxane B2 was higher in lymph than in plasma. Lymph flow rose from 8.7 to a maximum of 27.3 ml/h at 15 minutes but despite the increase in flow the lymph:plasma (L:P) protein ratio did not fall, indicating an increased permeability of the blood vessels to protein. Pretreatment with OKY 046 inhibited the rise in plasma and lymph thromboxane B2, and limited the rise of QS/QT. The changes in MPAP, PAWP, cardiac index, platelet count, lymph flow, and L:P protein ratio, however, were no different from those in untreated sheep. These results indicate that a large pulmonary embolus leads to an increase in plasma and lung lymph thromboxane A2, which moderates the rise in QS/QT in part but not the increase in vascular permeability.     

Effect of cryptorchidism on testicular and Leydig cell androgen production in the mouse

Unilateral cryptorchidism was induced surgically in adult mice and the effects on testicular and Leydig cell steroidogenesis were studied after 7 weeks. There was a 60% reduction in weight of the cryptorchid testis and this was associated with a significant reduction in intratesticular androgen content, both under basal conditions and following an injection of hCG. Testicular androgen production in vitro was also significantly lower in the cryptorchid testis compared to the scrotal testis, again under both basal conditions (29 +/- 6% of control) and in the presence of hCG (46 +/- 9% of control). Scrotal testes from the unilaterally cryptorchid animals did not show any significant difference in steroidogenic capacity compared to testes from untreated control animals. The decrease in steroidogenic capacity of the cryptorchid testis was due, at least in part, to a reduction in activity for each Leydig cell. In four experiments, androgen production by Leydig cells isolated from cryptorchid testes was 48 +/- 9% of cells from scrotal testes in the presence of a saturating dose of hCG. Under basal conditions the effect was more variable between experiments with steroid secretion by Leydig cells from cryptorchid testes being 58 +/- 32% of that for cells from scrotal testes. Leydig cell steroidogenesis in the scrotal testes of unilaterally cryptorchid animals did not differ significantly from untreated controls. These results show that induced cryptorchidism in the mouse causes a significant reduction in Leydig cell activity. This is apparently different from the effects of this procedure on the rat and raises the possibility that intratesticular regulation differs between the two species.     

A case of granulomatous orchitis

A 66-year-old man came to us with a chief complaint of painful right scrotal swelling. The right testis was enlarged on the ultrasound gray scale, but the inside was homogeneous. A power Doppler ultrasound showed slightly increased vascular flow in the periphery of the right testis. As the soluble IL-2 receptor was 527 U/ml (normal: 220-530 U/ml), we considered malignant lymphoma and performed high orchiectomy. On pathological examination, the tumor was diagnosed as granulomatous orchitis. To our knowledge, this is the 21st case in Japan.     

Prolonged suppression of rat testis function by a depot formulation of Zoladex, a GnRH agonist

A sustained-release formulation of a potent gonadotropin-releasing hormone (GnRH) agonist, Zoladex (D-Ser(But),6 Aza Gly10-GnRH; ICI 118,630; goserelin), was administered subcutaneously (3.6 mg/depot) to male rats once every 28 days for 2-24 wk to determine the extent to which pituitary-testis function could be suppressed and whether suppression was maintained throughout the period of treatment. Administration of Zoladex resulted in sustained decreases in weight of the testis, epididymis, seminal vesicles and prostate gland. The decreases were apparent within 2 wk of initiating treatment. Patchy degeneration of the seminiferous tubules and atrophy of the Leydig cells were observed, but did not progress beyond the degree observed after 1 month of treatment. Serum and testis testosterone were markedly depressed after 2 wk of treatment, as was testis [125I]hCG binding. Serum gonadotropins were also reduced by treatment. Serum androgen binding protein (ABP) was elevated, testis ABP content remained unchanged, and epididymal ABP content was reduced. The changes are consistent with the hypothesis that this compound affects both the anterior pituitary gland and the testis. These findings indicate that depot delivery systems are a convenient way to administer GnRH analogs for sustained treatment schedules.     

Clinical outcome of adult testicular tumor. I. Study on patients of nonseminoma with negative human chorionic gonadotropin

The outcome of clinical therapy of adult nonseminomatous testis tumor presenting with negative human chorionic gonadotropin (hCG) at our hospital is reported. Of 45 nonseminoma, 28 cases showed negative hCG and they had no chorionic element. Embryonal carcinoma was found in 14 cases (50%), teratoma in 5 cases (17.9%), and teratomatous mixed tumor in 9 cases (32.1%). The 5 year actuarial survivals were 94% for stage I disease, 40% for stage II and 16.6% for stage III. Prophylactic irradiation was given to the patient with stage I disease and no relapse occurred in the irradiated area, but later, neoplasms had spread by vascular dissemination in 3 cases (17.6%). In the treatment of stage II disease, radiotherapy has proved unsatisfactory and retroperitoneal lymph nodes dissection was a choice of modality. Of 11 patients with lung metastasis including vascular dissemination from stage II and III disease, 3 cases (27.3%) were cured by localized radiotherapy and chemotherapy of the pre-VAB regimen era.     

Effect of ibuprofen on the pulmonary and systemic response to repeated doses of endotoxin

We infused 10 doses of Escherichia coli endotoxin, 1 microgram/kg, during a 5-day period, into eight unanesthetized sheep with lung and systemic lymph fistulas. The animals were then monitored for an additional 5 days. We noted an attenuation of the lung microvascular permeability changes with the later endotoxin doses. However, a 50% increase in cardiac index and oxygen consumption and a leukocytosis were seen beginning with the ninth endotoxin injection; these persisted throughout the 15-day postendotoxin period, as did an increase in pulmonary artery pressure. The hyperdynamic state was present when plasma prostanoids were only modestly increased, and there was no evidence of increased lung or systemic vascular permeability. Postmortem lung findings, 5 days after endotoxin administration, showed a marked interstitial inflammatory response, with infiltration of macrophages, neutrophils, and some lymphocytes and an increase in interstitial fibrous tissue. Six sheep were then given ibuprofen, 12.5 mg/kg, intravenously before the ninth and tenth doses and on the subsequent day. Ibuprofen significantly attenuated the hyperdynamic state and the pulmonary hypertension. In addition, the lung inflammation and fibrous tissue deposition was markedly attenuated. We conclude that a systemic hyperdynamic state develops that corresponds in time with lung inflammation but not with increased permeability. The lung and systemic changes may be blocked by ibuprofen. The ibuprofen effect may be due to a response other than prostanoid production.