Hypoxic vasoconstriction in blood and plasma perfused lungs

Isolated lungs of pigs, cats and rats were perfused in situ with blood and with plasma at constant flow rate. The experiments were specifically designed to compare the intensity of the hypoxic pressor response (HPR) during blood and plasma perfusion. Ventilation of the lungs with 6.0% O2 during perfusion with blood, elevated the inflow pressure (Pa) from 18.9 +/- 1.5 to 35.8 +/- 2.0 mm Hg in pig lungs, from 12.9 +/- 0.5 to 17.9 +/- 1.1 mm Hg in rat lungs, and from 12.6 +/- 0.8 to 19.2 +/- 1.5 mm Hg in cat lungs. In comparison during perfusion of the lungs with plasma, the HPR was larger in pig lungs (Pa increased from 16.9 +/- 2.0 to 42.3 +/- 2.7 mm Hg), smaller in rat lungs (Pa increased from 10.2 +/- 0.9 to 11.4 +/- 1.2 mm Hg), and also smaller in cat lung (Pa increased from 9.9 +/- 1.2 to 11.9 +/- 1.2 mm Hg). The site of HPR in blood perfused cat lobes was primarily in the middle segment (arterial and venous technique) and remained in the middle segment (although blunted) during plasma perfusion. The vascular pressure-flow relationship in pig lungs showed that during blood perfusion, both the slope and intercept rose during hypoxia; these changes were similar but greater during plasma perfusion. Measurement of thromboxane A2 and prostacyclin in the lung effluent revealed no relation to intensity of the HPR or to the difference in the HPR in blood and plasma perfused lungs. Thus the absence of red blood cells (RBCs) may have been responsible for the difference in the HPR during blood and plasma perfusion; in rats and cats, RBCs appear to be essential for the full expression of the HPR, in contrast, the HPR in pigs does not require the presence of the RBCs. Possible explanations for these differences are suggested.     

Coronary vasoconstriction to endothelin-1 increases with age before and after ischaemia and reperfusion.

OBJECTIVE: Ageing is known to be associated with changes within the heart. We investigated whether the coronary response to endothelin-1 (ET) and sarafotoxin S6c (S6c) is altered with increasing age, before and after cardioplegic arrest. METHODS: Using an isolated rat heart model, increasing concentrations of ET and S6c were administered to rats of different ages (group I = one month; group II = five months; group III = 21 months). An identical series of experiments was performed following the addition of indomethacin and NG-nitro-L-arginine methyl ester (L-NAME) to the Krebs perfusion fluid. In a third series of experiments, increasing doses of ET-1 were added to hearts following 4 h of cardioplegic arrest at 4 degrees C. RESULTS: Coronary flows are expressed as a percentage of initial coronary flow +/- SEM. There was a greater decrease in coronary flow in the older rats for all doses of ET-1. ET-1 (10(-9) M) reduced coronary flows to 72.8 +/- 3.7, 53.2 +/- 6.7 and 56.5 +/- 10.7% for groups I-III respectively (P = 0.01 I vs. II; P = 0.1 I vs. III). A similar response to ET-1 was seen in hearts perfused with indomethacin and L-NAME when compared to those perfused without (P = NS). Perfusion with ET-1 (10(-9) M) following 4 h of cardioplegic arrest reduced coronary flows to 40.5 +/- 4.9, 26.8 +/- 4.8 and 24.1 +/- 3.9%, respectively (P = 0.08 I vs. II; P = 0.03 I vs. III). Perfusion with S6c (10(-10) M) produced coronary flows of 93.3 +/- 5.5, 77.0 +/- 3.5 and 73.9 +/- 3.9% for groups I-III, respectively (P = 0.03 I vs. II; P = 0.01 I vs. III). Perfusion with S6c (10(-9) M) in the presence of L-NAME and indomethacin reduced coronary flows to 85.7 +/- 3.0, 81.6 +/- 2.2 and 74.6 +/- 3.6% (P = NS I vs. II; P = 0.03 I vs. III). CONCLUSIONS: The coronary vasoconstrictor response to ET-1 and S6c increases with age. The increased vasoconstriction in response to ET-1 is independent of the decrease in NO release seen with ageing.     

FMLP causes eicosanoid-dependent vasoconstriction and edema in lungs from endotoxin-primed rats.

Recruitment of inflammatory cells to the lung capillaries has been proposed as an important step in the sequence of events that lead to acute lung injury. Frequently, in the clinical setting, bacteremia and sepsis syndrome precede the acute lung failure and endotoxin priming may represent a comparable paradigm, useful for experimental pursuit. Following addition of the chemotactic tripeptide FMLP (10(-9) to 10(-6) M) to the cell-free, salt solution perfusate of isolated rat lungs, only a small degree of vasoconstriction was observed. However, in lungs isolated from rats that received 2 mg/kg intraperitoneal Salmonella enteritidis endotoxin 2 h before lung perfusion, FMLP dose dependently caused a large, transient pulmonary pressor response, edema formation, and release of large amounts of thromboxane and leukotriene B4. Since in vitro priming with endotoxin, direct vascular injury by neutrophil elastase, nor direct stimulation with FMLP of pulmonary artery rings from endotoxin-pretreated rats, mimicked the effects of in vivo endotoxin priming, we conclude that the presence of inflammatory cells in the lung capillaries accounted for the large amount of eicosanoids produced by the lungs after FMLP stimulation. In fact, by retrograde lavage of the lung circulation with a collagenase solution, previously adherent cell clumps were mobilized and identified. These cell clumps, composed of red blood cells, neutrophils, and platelets, were not seen in the vascular lavage sediment obtained from unprimed control lungs. Indomethacin, a thromboxane antagonist, AA861, a 5-lipoxygenase inhibitor, and WEB 2086, a platelet-activating factor (PAF) antagonist, reduced the thromboxane synthesis and release after FMLP (10(-7) M) in in vivo endotoxin-primed lungs. None of the inhibitors employed exclusively inhibited only one particular eicosanoid mediator but rather affected the release of several mediators, suggesting a close link between the different synthetic arachidonic acid pathways. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), NCDC, but not an inhibitor of phospholipase D (Wortmannin) or of protein kinase C (staurosporine) inhibited the FMLP-stimulated pulmonary pressure rise and eicosanoid release in endotoxin-primed lungs in vivo. Our data suggest that eicosanoids (in particular thromboxane) released from cells trapped in the lung circulation, but not from constitutive lung cells, contribute to vasoconstriction and edema formation caused by the chemoattractant FMLP in endotoxin-primed lungs.     

Hypoxic pulmonary vasoconstriction in systemic sclerosis and primary pulmonary hypertension

Reduction of pulmonary vascular resistance by a high inspired oxygen concentration is a common, but not universal phenomenon in patients with pulmonary vascular disease of varying etiology that may determine their response to long-term domiciliary oxygen therapy. We therefore determined changes in PVR during oxygen therapy in two patient populations not previously studied: systemic sclerosis (n = 8, mean age +/- SEM, 44.5 +/- 5.4 years) and primary pulmonary hypertension (n = 7, mean age +/- SEM 38 +/- 7.8 years). All patients were hypoxemic (arterial oxygen tension, on air 9.5 +/- 1.2 kPa for SSc and 8.3 +/- 0.6 kPa for PPH, p greater than 0.05). Right atrial pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, systemic arterial pressure, PaO2 and cardiac output by thermodilution were measured at three, 20-min intervals while inspiring air and again after inspiring 60 percent oxygen for 30 min. The PVR fell significantly with oxygen in patients with SSc from 797.6 +/- 179.2 to 610 +/- 151.6 dynes/s/cm-5 (p less than 0.01), and this fall correlated with baseline PAP and PaO2 prior to oxygen therapy (r = 0.86, p less than 0.025; r = 0.77, p less than 0.05, respectively). In patients with PPH, there was no significant fall in PVR with oxygen (from 969 +/- 80.2 to 851.9 +/- 91.2 dynes/s/cm-5, p greater than 0.05) and no predictor of a vasodilator response in individual patients. In SSc, hypoxic pulmonary vasoconstriction contributes more consistently to elevated PVR than in patients with PPH.     

Hypoxic pulmonary vasoconstriction and pulmonary gas exchange in normal man

Blood gases, hemodynamics and ventilation were measured in 7 healthy volunteers at baseline while breathing room air (FIO2 0.21), during hypoxia (FIO2 0.125, 15 min) and after nifedipine 20 mg sublingually at FIO2 0.21 (45 min) and at FIO2 0.125 (15 min). Distributions of ventilation-perfusion ratios (VA/Q) were determined, using the multiple inert gas elimination technique, at baseline, during hypoxia, and again during hypoxia after nifedipine intake. Hypoxia was associated with an average increase in pulmonary vascular resistances by 104%, which was partially inhibited by nifedipine. The inert gas data showed a mild deterioration in the distribution of VA/Q ratios during hypoxia. However, when blood flow and ventilation were constrained to the baseline normoxic values in the distributions recovered during hypoxia ('normalization procedure') a slight improvement in VA/Q matching could be evidenced, which was blunted during hypoxia after nifedipine. This was interpreted as the functional effect of hypoxic pulmonary vasoconstriction (HPV). Using the 'normalized' distributions, we computed the relationship between the decrease in compartmental blood flow that occurred during hypoxia and the corresponding alveolar PO2, and calculated the gain due to HPV feedback using equations of the control theory. The contribution of HPV to the stability of compartmental VA/Q was greatest for alveolar PO2 values around 60 mm Hg, but at best the feedback had only a moderate efficiency.     

Proteoglycans from lungs of rabbits treated with pronase and cadmium chloride

The composition of proteoglycans was studied in lungs from rabbits treated intratracheally with pronase, CdCl2, or saline. Proteoglycans were extracted from the lungs by 0.5 M and 4.0 M guanidine hydrochloride (GdnHCl) in sequence. Proteoglycans were isolated from the extracts by CsCl isopycnic centrifugation and fractionated by gel filtration on a Sepharose CL-4B column. The lungs from pronase-treated rabbits had approximately 33% greater total uronate than did lungs from saline-treated control animals, whereas CdCl2-treated rabbit lungs had 28% less uronate than did control lungs. Pronase-treated animal lungs had a greater proportion of hyaluronic acid and dermatan sulfate than did the control animal lungs. Relatively greater amounts of uronate were extracted by 0.5 M GdnHCl from the enzyme-treated rabbit lungs than from the CdCl2- or saline-treated animal lungs. The concentrations of hyaluronic acid and heparan sulfate in 0.5 M GdnHCl extract and dermatan sulfate in 4.0 M GdnHCl extract were greater in pronase-treated animal lungs than in control lungs. Gel filtration of proteoglycans sedimented at q greater than 1.45 revealed that pronase-treated animal lungs had proteoglycans smaller in molecular size than those in control lungs. The observations indicate that intratracheal treatment with pronase and CdCl2 alters the composition of proteoglycans in the lung, and such alterations are likely important in the pathogenesis of emphysema.     

Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine

Objectives. The purpose of this study was to investigate whether therapy with nitroglycerin (GTN) would lead to abnormal coronary artery responses to the endothelium-dependent vasodilator acetylcholine.

Background. Nitroglycerin therapy is associated with specific biochemical changes in the vasculature that may lead to increased vascular sensitivity to vasoconstrictors.

Methods. Patients were randomized to continuous transdermal GTN, 0.6 mg/h (n = 8), or no therapy (n = 7), for 5 days prior to a diagnostic catheterization. Patients had similar risk factors for endothelial dysfunction. Quantitative angiography was performed in the morning to measure the mean luminal diameter of the left anterior descending coronary artery (LAD) in response to intracoronary acetylcholine (peak concentration, 10⁻⁴ mol/liter). The transdermal preparation was removed from the GTN group, and 3 h later experimental procedures were repeated.

Results. In the morning, the GTN group experienced greater coronary constriction in response to acetylcholine infusion than those not receiving GTN (−19.6 ± 4.2 vs. −3.8 ± 3.0%; p = 0.01). Three hours later, the GTN group continued to display greater constriction to acetylcholine (−24.1 ± 5.9%) as compared to the non-GTN group (−1.8 ± 4.8%). When the morning and afternoon responses to acetylcholine were compared, the increase in coronary constriction in the GTN group was greater than the change observed in the non-GTN group (p < 0.05).

Conclusions. This study demonstrates that therapy with GTN causes abnormal coronary vasomotor responses to the endothelium-dependent vasodilator acetylcholine, changes that were persistent for up to 3 hours after GTN discontinuation. This nitrate-associated vasomotor dysfunction has implications with respect to the development of nitrate tolerance and the potential for adverse events during nitrate withdrawal.     

Ethanol induces acute pulmonary vasoconstriction in salt-perfused rat lungs

Ethanol is a pulmonary vasoconstrictor in rat lungs perfused in situ with Krebs-Henseleit salt solution. Pentobarbital-anesthetized rats were tracheotomized, and an in situ recirculating isolated lung perfusion was instituted using a Krebs-Henseleit buffer with 3% bovine albumin at 37 degrees C. Changes in pulmonary arterial pressure and tracheal inspiratory pressure during intravenous ethanol infusion at four different cumulative doses were measured in normoxic (n = 6) and hyperoxic (n = 6) lungs, compared to normoxic perfusate (no ethanol infusion) controls (n = 6). Perfusate alcohol levels progressively increased in experimental groups. Perfusate gas and pH values were normal and not altered by ethanol. PAP increased by the end of ethanol infusion from 9.7 +/- 2 to 26 +/- 13 mm Hg in the normoxic group and from 10.6 to 22 +/- 9 mm Hg in the hyperoxic lungs (p less than .02); no change occurred in control lungs. Severe pulmonary edema occurred in 83% of the ethanol exposed lungs (vs. 0% of perfusate controls). Postethanol wet/dry weight ratios were twice normal (p less than .02). Pulmonary arterial pressure rose in two stages. First there was a 25-100% increase before airway pressure increased, representing pulmonary vasoconstriction. This was followed by a precipitous 100-500% transmitted pressure rise as severe pulmonary edema developed. Thus, we conclude that the vasoconstrictor effect of ethanol on the pulmonary circulation occurs in rats as well as in lambs, dogs, and humans. In isolated perfused rat lungs, the response is locally mediated.     

Acetazolamide reduces hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs

Carbonic anhydrase (CA) may modulate regional blood flow by mediating changes in extra- and intracellular pH. We hypothesized that CA inhibition with acetazolamide would inhibit the kinetics and magnitude of hypoxic pulmonary vasoconstriction (HPV). Isolated rabbit lungs were ventilated and perfused in situ at constant flow, with buffer containing red blood cells. Preparations were sequentially challenged with hypoxic (FI(O(2)) 0.05) and/or hypercapnic (FI(CO(2)) 0.10) gas mixtures for 5 or 10 min. In the experimental groups, acetazolamide (33 microM) was added to the perfusate after establishing baseline responses, and gas challenges were repeated; control groups were studied without acetazolamide. Acetazolamide reduced the increase in pulmonary artery pressure (DeltaPAP) and the rate of pressure rise by approximately 30-50% during hypoxia and combined hypoxia/hypercapnia. The reduction in DeltaPAP occurred for both 5 and 10 min challenges. Acetazolamide did not affect expired nitric oxide concentrations. We conclude that acetazolamide reduces both the magnitude and kinetics of HPV by a mechanism that does not involve nitric oxide.     

Lipopolysaccharide-induced neutrophilic inflammation in the lungs differs with age

In aged humans and animals, lung injuries are generally more serious and prolonged. From a kinetic perspective, the authors thus assessed whether lung expression of proinflammatory cytokines were altered with age following intratracheal lipopolysaccharide (LPS) challenge in mice. Tumor necrosis factor-alpha, interleukin-1beta, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-2, and keratinocyte-derived chemokine were significantly higher in 65-week-old mice along with sustained neutrophilia when compared to 11-week-old mice at 72 hours, but not at earlier time points. The authors concluded that the degree of LPS-induced neutrophilic inflammation and the expression of these cytokines differ with age at later phases of acute lung injury.     

Hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease

In patients with chronic obstructive pulmonary disease (COPD) studied at rest, nifedipine releases hypoxic pulmonary vasoconstriction (HPV) and worsens gas exchange. During exercise, this drug lowers pulmonary hypertension, but the effects of this lower pulmonary vascular tone on ventilation-perfusion (VA/Q) relationships are still poorly understood. To analyze them, we determined the VA/Q distributions in eight patients with stable COPD (FEV1, 36 percent of predicted) at rest and during exercise (60 percent VO2 max), before and after nifedipine (20 mg sublingually). Nifedipine shifted to the right the pulmonary pressure-flow relationship (p less than 0.01) and increased the dispersion of the blood flow distribution at rest and during exercise (p less than 0.005). These observations strongly suggest that nifedipine released HPV under both conditions. However, even after releasing HPV by nifedipine, exercise distributed blood flow more homogeneously than at rest (p less than 0.05). Besides, exercise greatly decreased the overall degree of VA/Q mismatching (p less than 0.001) not only before but also after nifedipine. Thus, we postulate that most of the VA/Q improvement that exercise may induce in patients with COPD, as it is shown here, is due to improvement in the ventilation distribution. Interestingly, this VA/Q improvement was not paralleled by a significant decrease of P(A-a)O2. This apparent paradox could be explained by 20 percent of the actual P(A-a)O2 during exercise due to diffusion limitation, as assessed through the inert gas approach. Taken all together, these results help to better understand the mechanisms that govern pulmonary gas exchange during exercise in COPD.     

Influences of diet and postnatal age on the lipid composition of red blood cell membrane in newborn infants

The fatty acid and cholesterol contents of tissue membranes are determinants of their stability and functionality. This study was designed to evaluate the influences of diet and postnatal age on the polyunsaturated fatty acid (PUFA) composition of erythrocyte membrane phospholipid fractions and on the red blood cell membrane cholesterol and phosphorus contents in newborn infants during the 1st month of life. A group of infants was fed on human milk and another group on adapted milk formula. Blood samples were obtained at birth, from cord blood, and at 7 and 30 days of age. Long-chain w6 PUFA declined with advancing age in all membrane phosphoglycerides and sphingomyelin (SM) in those infants fed formula. w6 PUFA also decreased in phosphatidylcholine (PC) and phosphatidylserine (PS) in infants fed human milk and were maintained constant in phosphatidylethanolamine (PE) and SM. w3 PUFA were less affected by postnatal age. PE and SM showed significantly higher percentages of w6 and w3 long-chain PUFA in infants fed human milk than in those fed formula. Membrane cholesterol content increased in all infants from birth to 1 month of life but phosphorus levels were unaffected by diet and postnatal age. These results suggest that diets with a low content of long-chain PUFA, such as adapted cow's milk formulas, may induce changes in membrane functionality and that incorporation of PUFA to the diet in amounts similar to those found in human milk should be considered at least in early life.     

Perinatal hypoxia increases hypoxic pulmonary vasoconstriction in adult rats recovering from chronic exposure to hypoxia

The possibility that perinatal exposure to hypoxia influences the pulmonary vasculature in adults was tested. Rats born in a hypoxic environment were kept in hypoxia for an additional week after birth. The rats were then raised in atmospheric air, and when adult, they were compared with the rats born and raised in air. Rats (10 wk old) of both groups were exposed to 10% O2 for 2 wk. They were then studied immediately after the exposure and after 2 wk of recovery from the sojourn in the hypoxic environment. The experience of perinatal hypoxia did not affect mean pulmonary arterial blood pressure, right ventricle weight, or the number of muscularized peripheral pulmonary vessels. During exposure to chronic hypoxia in adulthood, both groups developed pulmonary hypertension, which was not affected by previous perinatal hypoxia. The pulmonary vascular responses to acute hypoxic challenges were studied in the preparation of isolated perfused lungs. In both groups of rats, perinatally hypoxic and normoxic, the acute hypoxic vasoconstriction was attenuated immediately after the exposure of adult animals to chronic hypoxia. However, during the recovery from this hypoxic sojourn, the rats born in hypoxia were significantly more reactive to acute lung hypoxia than all other groups of rats studied. It is concluded that the experience of a short period of perinatal hypoxia did not affect the development of hypoxic pulmonary hypertension induced in adulthood. It increased, however, the pulmonary vascular reactivity to acute hypoxic stimuli during the period of recovery from a sojourn in the hypoxic environment in adulthood.     

Aging increases PGHS-2-dependent vasoconstriction in rat mesenteric arteries

During aging, the vascular endothelium changes functionally and morphologically. Although previous studies have shown that endothelium-derived eicosanoids increase vessel tone in aging, the precise mechanism(s) has not been fully determined. We hypothesized that aging would increase prostaglandin H synthase (PGHS)-dependent vasoconstriction as well as decrease nitric oxide-dependent relaxation. Mesenteric arteries from 3-month-old (n=9) and 12-month-old (n=14) female Sprague-Dawley rats were studied in a myograph system. Aging significantly blunted the endothelium-dependent relaxation response to methacholine compared with young rats (EC(50)=7.77x10(-8) versus 2.68x10(-8) mol/L, P<0. 05). Nitric oxide synthase inhibition reduced methacholine-induced relaxation in the young (P<0.05) but had no effect in the aging group. Specific inhibition of the PGHS-1 isoform did not significantly affect methacholine-mediated relaxation in the young or aged groups. However, PGHS-2 inhibition greatly enhanced relaxation to methacholine (1.59x10(-8) versus 7.77x10(-8) mol/L, P<0.01) in the aged group only, restoring vessel function to that of the young. In the aged group, inhibition of the prostaglandin H(2)/thromboxane A(2) receptor enhanced methacholine-dependent relaxation similar to that of PGHS-2 inhibition. Moreover, arterial expression of PGHS-2 protein increased with age. In summary, nitric oxide-dependent modulation of vessel function decreased with age, PGHS-1 did not significantly affect vessel tone in either the young or aging group, and PGHS-2 greatly increased vasoconstriction in aging. Thus, we have identified enhanced PGHS-2-mediated vasoconstriction in aging and therefore suggest that inhibition of this isoform is potentially a new target for therapeutic intervention to improve vascular function.     

Ventilation techniques to minimize circulatory depression in rabbits with surfactant deficient lungs

Changes in aortic blood flow were measured in rabbits with both normal and surfactant depleted lungs in order to elucidate the effect of different modes of ventilation on the circulation while optimizing arterial oxygenation (P_ao2). Conventional mechanical ventilation (CMV), reversed inspiratory to expiratory ratio of CMV (IRV), high frequency positive pressure ventilation (HFV), and high frequency oscillation (HFO) were used. Normocapnia was maintained throughout during different modes of ventilation. In normal lungs the aortic blood flow during IRV was significantly lower with similar levels of P_aO2 compared with CMV, HFV, and HFO. In lavaged lungs, without positive end-expiratory pressure (PEEP), the aortic blood flow during CMV was significantly higher than with other modes of ventilation. When 10 cm H₂O of PEEP was applied, the P_ao2 increased maximally to normal values at all modes of ventilation, but the aortic blood flow was significantly reduced (P < 0.05) during CMV and IRV compared to HFV and HFO. The aortic blood flows at 5 cm H₂O of PEEP were very similar during CMV, HFV, and HFO but significantly reduced during IRV. This study showed that at an optimal arterial oxygenation with higher PEEP levels, maintenance of aortic blood flow was maximal during HFV and HFO. Pediatr Pulmonol. 1994;18:317–322 © Wiley-Liss, Inc.     

Incidence of apoptosis increases with age in colorectal cancer

The incidence of cancer increases with advancing age, but the biological behavior of cancer is known to be less aggressive in elderly people. Thus, the proliferative activity and extent of apoptosis of cancer cells were assessed in samples from 163 cases of colorectal cancer focusing on the age of patients, using Ki-67 labeling index (LI) and apoptotic index (AI) by terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP nick end labeling method and staining for activated caspase-3.

The Ki-67 LI of colorectal cancer ranged from 2.33 to 80.4% (mean 32.2%), while the AI ranged from 0.00 to 14.8% (mean 3.57%). Concerning the aging effect, linear and positive correlations were found for the Ki-67 LI of cancer with age (p<0.05) and the AI of cancer with age (p<0.05). However, in normal colorectal mucosa, aging of patients revealed a significant correlation only with the AI but not with the Ki-67 LI. The AI in earlier stages of cancers (stages 0 and 1) revealed a significant difference between younger cases (age<65) and more elderly cases (age≥65) (p<0.05), however, the Ki-67 LI did not exhibit a significant difference. Therefore, an increased frequency of apoptosis in colorectal cancer tissues, especially in the earlier stages, may possibly explain the slower growth of colorectal cancers in the elderly. Next, the expressions of several regulatory molecules for the proliferation/apoptosis of tumor cells were determined. The results demonstrated a tendency for stronger and more frequent expressions of c-myc, Bak and Bax despite a rather weaker expression of Bcl-2 in cancer tissues from the elderly compared with those from the younger patients. The potential roles of these regulatory molecules on age-change in the proliferation/apoptosis of colorectal cancers are discussed.