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Biomedical subjects

M G Clemens

Publications and source records attributed to M G Clemens.

At least 19 recordsLinked to original sources
PubMed2001

Altered endothelin receptor expression in prehepatic portal hypertension predisposes the liver to microcirculatory dysfunction in rats.

BACKGROUND/AIMS: Endothelin (ET) is one of the most active vascular regulators in the liver. It is unknown how partial portal vein ligation (PPVL) induced prehepatic portal hypertension influences the response of the liver to ET and its agonists. Therefore, this study was conducted to determine the expression of ET receptors and its functional significance after PPVL. METHODS: Competitive receptor binding study and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) were performed using liver homogenates after 2 weeks of PPVL or sham operation in rats. Hepatic microcirculation was evaluated in vivo using intravital microscopy. RESULTS: Although there was no significant difference in dissociation constant (Kd) and total amount of receptors (Bmax) between sham and PPVL, the proportion of ET(B) receptor was significantly increased in PPVL. RT-PCR analysis confirmed the up-regulation of ET(B) receptors demonstrated by the competitive receptor binding assay. In the functional study, infusion of ET(B) agonist (IRL 1620) in a low dosage did not change the hepatic microcirculation in sham but strongly constricted the sinusoids leading to a reduction of sinusoidal perfusion in PPVL. CONCLUSIONS: These results suggest that prehepatic portal hypertension may predispose the hepatic microcirculation to dysregulation in stress conditions where ET is upregulated.

Animals↗
PubMed2001

In vivo assessment of endothelin-induced heterogeneity of hepatic tissue perfusion.

Specific vasoactive substances such as endothelin (ET) have been proposed to induce heterogeneity of tissue perfusion and thus the oxygen delivery at the sinusoidal level in the liver, but a direct method for testing this hypothesis has not been available. Our objective was to develop a method to test the hypothesis that functional heterogeneity of blood flow can be induced at the sinusoidal level by mediators such as endothelin-1, which act at the sinusoidal level. We constructed oxygen-sensitive membranes using tris (1,10-phenanthroline) ruthenium (II) chloral hydrate, a dye whose fluorescence is quenched by oxygen incorporated into a silicon rubber membrane. The membrane (less than 40 microm thick) was formed on a glass coverslip that served as the viewing window of the system for in vivo fluorescence microscopy and allowed determination of the PO2 distribution in rat liver acini during intraportal infusion of ET or phenylephrine (PE) in vivo. Heterogeneity was quantified by comparing the coefficient of variation (CV) of the fluorescence intensity within the zone 1 before, during, and after drug infusion. PE and ET doses were matched to produce a similar increase in portal pressure. PE caused a gradient of PO2 across zones, but within zone 1 no significant increase in CV was observed. In contrast, ET produced a patchy pattern of both an increase and decrease in PO2 resulting in doubling (P < 0.01) in CV of fluorescence intensities within zone 1. These results indicate that PE, which acts at presinusoidal sites, results in a homogeneous decrease in tissue PO2 within a zone, while ET, which additionally acts at sinusoidal sites, induces significant microheterogeneity of tissue PO2. The oxygen-sensitive membrane provides a useful tool for oxygen mapping in vivo.

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PubMed2001

Hepatic neovascularization after partial portal vein ligation: novel mechanism of chronic regulation of blood flow.

The present study was undertaken to investigate hepatic microcirculatory response following partial portal vein ligation (PPVL) in rats. Portal pressure was markedly increased 2-6 wk after PPVL, but no significant reduction in sinusoidal perfusion and hepatocellular injury were detected. However, marked neovascularization was observed in PPVL rats using intravital microscopy and scanning electron microscopy (SEM). Extremely high red blood cell velocity (2,000-4,900 microm/s) was seen in these vessels. Injection of fluorescein sodium via the carotid artery revealed that the neovessels originated from the hepatic arterial vasculature. This was further confirmed by clamping the common hepatic artery and phenylephrine injection from the carotid artery. These vessels maintained sufficient flow after massive sinusoidal shutdown elicited by the portal infusion of endothelin receptor B agonist IRL-1620. SEM also showed extensive neovascularization at the hilum. Additionally, clamping the portal vein decreased sinusoidal perfusion only by 9.5% in PPVL, whereas a 71.2% decrease was observed in sham. These results strongly suggest that the liver maintains its microcirculatory flow by vascular remodeling from the hepatic arterial vasculature following PPVL.

Alanine Transaminase↗
PubMed2000

Functional significance of endothelin B receptors in mediating sinusoidal and extrasinusoidal effects of endothelins in the intact rat liver.

Endothelins (ET) are important regulators of the hepatic microcirculation that act through different receptor subtypes. We investigated functional significance of ET(B) receptors in mediating microhemodynamic effects of ETs in normal and endotoxin (lipopolysaccharide [LPS])-primed rat liver. LPS priming (Escherichia coli O26:B6; 1 mg. kg(-1)) selectively increased ET(B) mRNA and led to a shift in available receptors to the ET(B) subtype. IRL 1620 (an ET(B) agonist) increased portal pressure in a dose-dependent manner, and the increase in ET(B) expression was associated with prolonged portal pressor response in isolated livers. However, lactate dehydrogenase (LDH) release was attenuated and sinusoidal blood flow was better maintained upon ET(B) stimulation in vivo. In isolated livers, portal constriction as well as release of LDH, were substantially increased in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS). In vivo microscopic assessment of sinusoidal perfusion during ET(B) stimulation revealed a disruption of the flow pattern including frequent reversal of the flow direction without significant sinusoid constriction. Sinusoidal flow decreased even further after discontinuation of IRL 1620. Both effects were mediated at extrasinusoidal sites that probably included postsinusoidal sites. However, after pretreatment with L-NAME, IRL 1620 evoked a significant sinusoidal constriction that colocalized with the body of the stellate cell. We propose that ET(B1)-induced NOS activity attenuates ET(B2) (and presumably ET(A))-mediated portal pressor response and stellate cell constriction. Transcriptional activation of the ET(B) gene may have a permissive effect on liver blood flow and protect against hepatocellular damage under pathophysiological conditions associated with endotoxemia.

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PubMed2000

Hepatic injury and lipid peroxidation during ischemia and reperfusion.

We determined the relationship between lipid peroxidation and alterations in hepatic secretory and microsomal function during various periods of hepatic ischemia/reperfusion. Rats were pretreated with alpha-tocopherol or vehicle and then subjected to 30, 60, and 90 min, no-flow hepatic ischemia in vivo with 1 or 5 h of reperfusion. Serum aminotransferase (ALT) level, wet-dry weight ratio, and lipid peroxidation were increased at 1 and 5 h of reperfusion, and these changes were significantly attenuated by alpha-tocopherol. Na+, K+-ATPase activity, and glucose-6-phosphatase activity were significantly decreased in 90-min ischemic rats, and these decreases were ameliorated by alpha-tocopherol. After 90 min of ischemia, bile flow, cholate output, and bilirubin output were markedly decreased by ischemia/reperfusion, and alpha-tocopherol restored the secretion. Cytochrome P450 content was decreased by ischemia/reperfusion and restored by alpha-tocopherol to the level of that found in the sham-operated group. Aminopyrine N-demethylase activity was decreased, and aniline p-hydroxylase was increased in 60-min ischemic rats. The changes in the activities of the two enzymes were prevented by alpha-tocopherol. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory functions and microsomal drug metabolizing systems in proportion to the duration of ischemia and reperfusion in vivo, and this is associated with increased lipid peroxidation.

Alanine Transaminase↗
PubMed2000

Altered endothelin receptor subtype expression in hepatic injury after ischemia/reperfusion.

This study was performed to determine whether ischemia/reperfusion (I/R) injury in rat liver results in alterations in endothelin receptor expression. Hepatic ischemia was produced in rats for 60 min followed by 6 or 24 h reperfusion. Portal inflow pressure was increased (7.38+/-0.60 mmHg) at 24 hours after reperfusion. Serum ALT increased significantly at both 6 and 24 h (6 h; 258.3+/-74.3, 24 h; 243.1+/-74.8 IU/L). Portal vascular response to an endothelin-B receptor agonist (IRL 1620) was significantly increased in the I/R livers compared to control and this was potentiated by L-NAME. IRL 1620 also caused LDH release from I/R livers but not controls. LDH release after IRL 1620 in I/R livers correlated with increased portal pressure response. To determine whether the altered response might be the result of altered endothelin receptor expression, livers were harvested after reperfusion and total endothelin binding sites were determined by competitive binding with ET-1. Proportion of endothelin receptor subtypes (ET(A)/ET(B)) was determined using the ET(A) antagonist BQ-610 (1 microM) and ET(B) agonist IRL-1620 (100 nM). There were no significant changes in Kd but Bmax for endothelin-1 was decreased in I/R group especially non-ischemic lobe at 24 h. ET(A) receptors were significantly decreased whereas ET(B) receptors were increased. These changes were more pronounced at 24 h after reperfusion than at 6 h. Interestingly, the changes in ET receptors was observed identically both in ischemic and non-ischemic lobes (ischemic lobe ET(A) 41.9%, ET(B) 51%; non-ischemic lobe ET(A) 38.8%, ET(B) 49.5%). These results indicate that the major functional endothelin receptor subtype upregulated in I/R is the ET(B) receptor and that this upregulation may contribute to microvascular dysregulation and hepatic injury.

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PubMed2000

Interruption of hepatic gap junctional communication in the rat during inflammation induced by bacterial lipopolysaccharide.

Gap junctional cellular communication is important in the propagation of signals that coordinate hepatic metabolism. Hepatocytes express two different connexin (Cx) genes, Cx32 and Cx26, which encode for the subunit component of gap junction channels. Previous studies have shown that the expression of hepatic Cx32 is reduced during inflammatory conditions. The objective of this study was to evaluate whether this decrease in Cx32 expression results in a decrease in hepatic gap junctional communication. Transfer of the dye Lucifer Yellow between hepatocytes was measured after microinjection of single cells in an isolated perfused liver. Livers were harvested from rats subjected to an inflammatory condition induced by administration of bacterial lipopolysaccharide (LPS). A decrease in gap junctional cellular communication was observed within 6 h of the LPS treatment. This decrease in dye coupling was reversible, because gap junctional communication returned to control levels within 48 h of the LPS injection. The inhibition of hepatic gap junctional communication was associated with the disappearance of Cx32 and Cx26 from the hepatocyte plasma membrane as detected by indirect immunostaining. Cx32 mRNA levels were also reduced during inflammation as previously reported. However, Cx26 mRNA levels were unaffected or even transiently increased after the injection of LPS without significant increase in the polypeptide level. Thus, the down-regulation of Cx32 and Cx26 from the hepatocyte surface is apparently due to a rapid degradation of the polypeptide from the cell surface. We hypothesize that this loss of gap junctional cellular communication within the liver may contribute to the disordered hepatic metabolic that occurs during inflammatory states.

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PubMed1999

A synergistic effect of extracellular hypocalcemic condition for hyperoxic reoxygenation injury in rat hepatocytes.

BACKGROUND: Calcium accumulation of cells and mitochondria during reperfusion or reoxygenation has been implicated as a potential factor in cell injury as the result of mitochondrial damage. The objective of this study was to disclose whether or not low extracellular calcium ion concentration ([Ca2+]ex) in the medium at the time of reoxygenation might prevent calcium accumulation and attenuate hepatocytes injury after severe hypoxia. METHODS: Isolated rat hepatocytes were incubated under a hyperoxic or hypoxic atmosphere for 60 min. During the ensuing 60-min hyperoxic reoxygenation, medium [Ca2+]ex was varied from 0.6 microM to 2.0 mM by altering total calcium and addition of chelators. RESULTS: Incubation in low [Ca2+]ex reduced total cellular calcium and mitochondrial calcium in both the hyperoxic and hypoxic group. Under hyperoxic/hyperoxic incubation (control), hepatocytes were able to maintain potassium balance when [Ca2+]ex was >3.0 microM (pCa=5.5) and cellular viability (% lactate dehydrogenase release) at all levels of extracellular calcium. Under hypoxic/hyperoxic incubation (reoxygenation), however, loss of the ability to restore potassium balance as well as apparent increase in lactate dehydrogenase release were observed at severely low [Ca2+]ex (<30 microM; pCa=4.5). This low [Ca2+]ex-induced exacerbation of hepatocytes viability could not be generated under mild reoxygenation such as normoxia. CONCLUSIONS: In normal isolated hepatocytes, very low [Ca2+]ex levels produce only very subtle changes in membrane permeability of isolated hepatocytes. After hypoxia, however, hypocalcemia acts synergistically with hyperoxic reoxygenation to produce more severe damage. These results suggested that [Ca2+]ex should be maintained on the physiological level to attenuate hepatocytes injury after severe hypoxia.

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PubMed1999

Regulation of sinusoidal perfusion: in vivo methodology and control by endothelins.

Considerable attention has recently been focused on the phenomenon of active constriction of sinusoids as a mechanisms for regulating perfusion of the liver. Although many methods for estimating liver blood flow have been used in the past, the ability to directly study vascular responses in the sinusoids required the spatial and temporal resolution provided by intravital microscopy. Although techniques for viewing microvessels in thin tissues such as the mesentery or cremaster muscle have been available for many years, our current ability to fully use intravital microscopy to study microvascular responses and related metabolic parameters in thick tissues such as the liver has resulted from recent advances in fluorescence microscopy. Intravital microscopy can be used in in vivo or isolated perfused liver studies to assess changes in sinusoidal perfusion. Additional information concerning the relationship between microvascular changes and metabolic parameters in the liver can be simultaneously obtained by exploiting various recent advances in the design of fluorescent indicators. These techniques have allowed the mechanisms regulating sinusoid perfusion to be studied in great detail. It is now clear that sinusoids constrict in vivo in a graded and reversible manner in response to specific mediators such as endothelins. This constriction is modulated by dilators such as nitric oxide and carbon monoxide, which are also generated within the sinusoids. It is likely that poorly regulated sinusoid constriction contributes to liver injury and long-term development of increased intrahepatic vascular resistance. This response is mediated by alterations in the expression of endothelin receptor subtypes and eventually by phenotypic transformation of the hepatic stellate cells. In addition, local mismatch in the stress-induced induction of vasodilator and vasoconstrictor influences lead to an increase in the local heterogeneity of blood flow and oxygen supply. This heterogeneous perfusion contributes to the development of focal ischemia and progression of injury. Taken together, the results reviewed here indicate that the sinusoid is an important site of regulation of liver blood flow and that dysregulation of sinusoidal perfusion leads to propagation of liver injury.

Animals↗
PubMed1999

Patterns of vasoregulatory gene expression in the liver response to ischemia/reperfusion and endotoxemia.

Oxidative stress and inflammatory reactions associated with stresses that may lead to shock promote hepatic microcirculatory dysfunction, which may lead to hepatic injury. Because altered liver microcirculation may result from an imbalance in the expression of stress-induced vasoactive mediators, our study was conducted to investigate changes in the expression of genes encoding endothelin-1 (ET-1), its receptors, ET(A) and ET(B), heme-oxygenase 1 (HO-1), and inducible nitric oxide synthase (iNOS), using two different rat models of liver stress: ischemia/reperfusion of the liver and lipopolysaccharide (LPS)-induced endotoxemia. In ischemia/reperfusion experiments, rats were subjected to 1 h hepatic ischemia, followed by 6 h of reperfusion. Endotoxemia was induced by i.p. injection of LPS (1 mg/mL/kg body weight); rats were studied after 6 h. mRNA levels were estimated using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on total RNA samples prepared from experimental and sham control rat livers. In the ischemic reperfused livers the levels of mRNA for ET-1, ET(B), HO-1, and iNOS were significantly elevated. The fold increase versus sham was 2.5+/-1.1 (ET-1), 2.1+/-1.3 (ET(B)), 2.1+/-.8 (HO-1), and 6.4+/-3.9 (iNOS). In contrast, the expression of ET(A) receptor gene was reduced after ischemia/reperfusion (to 73+/-1% of sham). In the separate experiments we analyzed the same mRNAs levels after 1 h of ischemia (no reperfusion), and did not detect any changes. During endotoxemia we observed a marked increase in iNOS mRNA level (>24-fold), as well as a marked elevation of the other four mRNAs. The fold increase versus sham was 6.1+/-1.7, ET-1); 1.5+/-.3 (ET(A)); 1.6+/-.4 (ET(B)); and 2.4+/-.34 (HO-1). These results show that liver stress, induced by ischemia/reperfusion or LPS injection have characteristic patterns of vasoregulatory genes expression indicating that, although both stresses result in an increase in specific vascular reactivity, different pathways are involved in inducing the hepatic vascular stress response.

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PubMed1999

Ischemia/reperfusion induces an increase in the hepatic portal vasoconstrictive response to endothelin-1.

Microvascular impairment observed during reperfusion following ischemia (IR) is a major determinant of the development of liver injury. Previous studies have shown that hyper-responsiveness to endothelin-1 (ET-1) contributes to microvascular dysfunction following a primarily inflammatory stress induced by endotoxin. The present study investigates whether a similar hypercontractile response to ET-1 occurs in the hepatic portal system of IR rats. Pentobarbital-anesthetized Sprague-Dawley rats underwent liver ischemia of the left and medial lobes for 60 min (IR: n = 8) or a sham operation (n = 8). Six hours after reperfusion, the liver was isolated and perfused through the portal vein. Baseline portal pressure (Pp), portal flow (Qp), and sinusoidal diameter (Ds) were measured before and 3 and 10 min after adding ET-1 (1 nM). In baseline, IR livers had a significantly greater Pp, portal resistance, and Ds than sham. ET-1 significantly increased Pp and portal resistance and significantly decreased Qp and Ds in IR and sham rats. However, these effects were significantly greater in IR. The results of the present study demonstrate that IR increases the porto-hepatic contractile response to ET-1, which may further sensitize the portal circulation to elevated ET-1 and may be a prominent contributor to the development of microvascular impairment following IR.

Animals↗
PubMed1999

Inhibition of poly(ADP-ribose) synthetase improves vascular contractile responses following trauma-hemorrhage and resuscitation.

Hyporeactivity of vessels to constrictor agents is thought to contribute to cardiovascular decompensation following trauma-hemorrhage and resuscitation. In this study, we determined if inhibition of poly(ADP-ribose) synthetase (PARS) activity prevented the development of vascular hyporeactivity in rats following trauma-hemorrhage and resuscitation. Trauma consisted of a laparotomy that was closed and rats were hemorrhaged into a reservoir containing citrate to 40 mm Hg for 90 min. Resuscitation included 2/3 of the shed blood plus 2 1/3 of the shed volume as Ringer's lactate. Sham animals received the laparotomy and were time-matched. Induction of iNOS was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Aortic rings isolated 6 h after the initiation of hemorrhage (4.5 h after resuscitation) showed decreased responsiveness to norepinephrine (peak developed tension 0.31+/-0.01 g/mg tissue) compared with sham rings (0.43+/-0.02 g/mg tissue), but no change in EC50 for this response (approximately 5x10(-8) M). Addition of the PARS inhibitor, 3-aminobenzamide, at the onset of resuscitation prevented the decrease in response of aortic rings. The addition of the structural analogue, 3-aminobenzoic acid, which does not inhibit PARS, did not prevent the decrease in vascular reactivity. These agents did not alter vascular responses to norepinephrine in sham animals. iNOS induction was not associated with depressed contractile function. These results indicate that decreased vascular reactivity was prevented by inhibition of PARS and that PARS activation was independent of iNOS induction following trauma-hemorrhage and resuscitation.

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PubMed1998

Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats.

Maintenance of hepatic microcirculatory flow after ischemia of the liver is essential to prevent hepatic dysfunction. Thus, we determined the differential role of carbon monoxide (CO) and nitric oxide (NO) in the intrinsic control of sinusoidal perfusion, mitochondrial redox state, and bile production in the isolated perfused rat liver after hemorrhagic shock. Administration of tin protoporphyrin-IX (50 microM), a specific inhibitor of the CO generating enzyme heme oxygenase, caused a decrease in sinusoidal flow that was more pronounced after shock compared with sham shock, as determined by in situ epifluorescence microscopy. This was associated with a shift in hepatocellular redox potential to a more reduced state (increased fluorescence intensity of reduced pyridine nucleotides in hepatocytes, decreased acetoacetate/beta-hydroxybutyrate ratio in the perfusate) and a profound reduction in bile flow. In sharp contrast, the preferential inhibitor of the inducible isoform of NO synthase S-methylisothiourea sulfate (100 microM) did not affect sinusoidal flow, hepatic redox state, or function. This indicates that 1.) endogenously generated CO preserves sinusoidal perfusion after hemorrhagic shock, 2.) protection of the hepatic microcirculation by CO may serve to limit shock-induced liver dysfunction, and 3.) in contrast to CO, inducible NO synthase-derived NO is of only minor importance for the intrinsic control of hepatic perfusion and function under these conditions.

Animals↗
PubMed1998

Role of endothelins and nitric oxide in hepatic reperfusion injury in the rat.

We determined the functional role of nitric oxide (NO) and endothelins (ET), two potent vasoactive mediator systems in the liver, for the pathogenesis of sinusoidal perfusion failure and lethal hepatocyte injury after low-flow ischemia/reperfusion in the isolated perfused rat liver. NO synthase blockade with Nomega-nitro-L-arginine methyl ester (L-NAME) (10[-3] mol/L) before reperfusion prevented increased N02-/NO3- the final products of NO oxidation, which could be observed in the vehicle group. Epifluorescence microscopy revealed that the decrease in functional sinusoid density during reperfusion was much more profound compared with vehicle. This was associated with a lower surface PO2, a substantially higher number of nonviable hepatocytes, as assessed by in situ propidium iodide staining, and enhanced enzyme release into the perfusate compared with vehicle. In contrast, reperfusion in the presence of the endothelinA+B receptor antagonist bosentan (2 x 10(-4) mol/L) restored functional sinusoid density and surface PO2 to baseline values, resulted in a small reduction in the number of propidium iodide-positive hepatocytes, and caused similar increases in enzyme release as compared with vehicle. This indicates that hepatic generation of NO attenuates sinusoidal perfusion failure and improves liver tissue oxygenation, thus limiting hepatocyte injury during early reperfusion after hepatic low-flow ischemia. In contrast, endothelins counteract the microcirculatory effects of NO, i.e., mediate the no-reflow in hepatic sinusoids; however, the restoration of functional sinusoid density with bosentan resulted only in a small reduction in tissue damage, suggesting that additional components, which are independent of microcirculatory failure, contribute to hepatic reperfusion injury under these conditions.

Animals↗
PubMed1998

Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver.

Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXa, iron, and carbon monoxide. The HO-system consists of two isoenzymes, namely HO-2 and the inducible isoform HO-1, also referred to as heat shock protein (hsp) 32. Although both parenchymal and non-parenchymal liver cells participate in heme metabolism, the expression pattern of the isoenzymes in normal and stress exposed liver is unknown. To study this, rats underwent either endotoxin (lipopolysaccharide [LPS]) challenge, hemorrhagic hypotension, glutathione (GSH) depletion, or cobalt chloride injection, all known to provoke oxidative stress. HO-2 messenger RNA (mRNA) and protein were constitutively expressed in hepatocytes, Kupffer/endothelial-, and stellate (Ito-) cell enriched fractions. Although both non-parenchymal cell fractions expressed HO-1 transcripts, HO-1 immunoreactive protein was restricted to Kupffer cells in the normal liver. In contrast to HO-2, a significant increase in HO-1 on the whole organ level was noted by hemorrhagic hypotension, GSH depletion, and cobalt chloride injection. However, the distinct stress models led to a strikingly different cell-type specific and sublobular expression pattern of HO-1 gene expression. HO-1 was inducible in sinusoidal lining cells (hemorrhagic hypotension, LPS challenge), in periportal (cobalt chloride), or pericentral (GSH depletion, hemorrhagic hypotension) hepatocytes. The blockade of protein translation before hemorrhage by cycloheximide reduced upregulation of HO-1/hsp32 mRNA significantly (65.4% reduction, P < .05), whereas the inducibility of hsp70 transcript was maintained. In addition to transcriptional regulation, HO-1 seems to be subject to posttranscriptional control in particular in non-parenchymal cells.

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