Biomedical subjects

R P Michel

Publications and source records attributed to R P Michel.

At least 19 recordsLinked to original sources

PubMed2001

Elevation of CA-125 level is due to abdominal distension in liver transplantation candidates.

BACKGROUND: CA (cancer antigen) 125 is a serologic marker used in the monitoring of ovarian cancer. Elevated levels are also reported in cirrhosis. We evaluated the range of serum CA 125 levels seen before and after liver transplantation, and examined possible factors associated with CA 125 elevation. METHODS: We examined prospectively 57 consecutive patients with cirrhosis who underwent liver transplantation. CA 125 levels were also measured in two patients with polycystic liver disease. RESULTS: The mean serum CA 125 level before transplantation was 352+/-549 u/ml, compared with 46+/-49 u/ml after transplantation (P<0.001). Multivariate analysis identified the degree of ascites as the only significant predictive variable of preoperative CA 125 level. In five patients who underwent abdominal paracentesis, the mean ascites CA 125 level (951+/-322 u/ml) was higher than that of the serum (619+/-290 u/ml) (P<0.003). In 16 hepatectomy specimens, the grade of staining for CA 125 was 0.8+/-1.4 for the mesothelium of patients with a normal serum CA 125 level, compared with 1.5+/-1.1 in patients with elevated serum levels (P=0.37). Two patients with severe abdominal distension due to polycystic liver disease but without ascites had elevated serum CA 125 levels. DISCUSSION: CA 125 concentration is elevated in the majority of patients with cirrhosis and normalizes after liver transplantation. It is a reflection of the abdominal distention seen in these patients. Therefore, an elevation in CA 125 should not be considered a contraindication to liver transplantation in the absence of evidence of malignancy.

Ascites↗

PubMed2001

Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis.

OBJECTIVE: To identify the prognostic significance of certain clinical, cellular and immunologic markers in resectable non-small cell lung cancer (NSCLC). DESIGN: A cohort of patients with resectable NSCLC was prospectively followed up for 8 years (100% follow-up). SETTING: A university hospital in a large Canadian city. PATIENTS: One hundred and thirteen consecutive patients who underwent surgical resection of primary NSCLC. MAIN OUTCOME MEASURES: Presence of peritumoral B lymphocytes (identified with antibody to CD20) and T lymphocytes (antibody to CD43), along with tumour markers (carcinoembryonic antigen [CEA], keratin, cytokeratin, S-100 protein, vimentin, chromogranin) and other factors such as age, sex, cell type, American Joint Committee on Cancer (AJCC) stage, histologic grade, DNA ploidy and S-phase fraction were correlated with survival. RESULTS: The mean age of patients in the study was 66.0 years; 60% were male. Histologic types of the tumours were: adenocarcinoma 57 (50.4%), squamous cell 47 (41.6%), adenosquamous 6 (5.3%) and large cell 3 (2.6%). AJCC stages were: I 66 (58.4%), II 20 (17.7%) and III 27 (23.9%). Histologic grades were: I (well differentiated) 31 (27.4%), II 50 (44.2%), III 29 (25.7%) and IV 3 (2.6%). Survival was 85% at 1 year (95% confidence interval [CI] 76%-90%), 44% at 5 years (95% CI 34%-53%) and 34% at 10 years (95% CI 22%-46%). Multivariate analyses using the Cox proportional hazards model for survival confirmed AJCC stage (p < 0.001) in all histologic subtypes to be the strongest factor of independent prognostic significance. It also revealed the presence of CD20-stained B lymphocytes (p = 0.04) in the peritumoral region of all tumours to be a positive prognostic factor. This relation was especially strong for nonsquamous cell carcinomas (p < 0.001). For squamous cell carcinomas, the immunohistochemical presence of CEA was of marginally negative prognostic value (p = 0.04). DNA ploidy and a high S-phase fraction showed no evidence of prognostic value for stage I tumours, but for stages II and III tumours there was strong evidence of prognostic value (p < 0.001 jointly). The evidence for DNA ploidy was especially strong in stages II and III squamous cell tumours (p = 0.008), and for a high S-phase fraction was strongest in stages II and III nonsquamous cell tumours (p = 0.002). CONCLUSIONS: AJCC stage remains the most important prognostic indicator from a variety of clinical variables and tumour markers in postoperative patients with resectable NSCLC. For nonsquamous cell lung carcinomas, the presence of peritumoral B lymphocytes was strongly associated with improved survival, suggesting an important role for humoral mediated immunity.

Adult↗

PubMed2000

Altered reactivity of pulmonary vessels in postobstructive pulmonary vasculopathy.

Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling and bronchial angiogenesis, collectively known as postobstructive pulmonary vasculopathy (POPV). To investigate pulmonary vascular reactivity in POPV, we ligated the left main pulmonary artery of guinea pigs and, after 1-10 mo, prepared explants by inflating lungs with agarose and sectioning them into approximately 1-mm-thick slices; we measured areas of pulmonary vessels and determined contractile responses to histamine and serotonin (5-HT) and relaxant responses to ACh and sodium nitroprusside. We found maximal contractions of arteries to 5-HT (24. 4 +/- 2.6%) and of veins to histamine (53.9 +/- 4.7%) were significantly increased in POPV of 3-mo duration compared with those of controls (16.8 +/- 1.5 and 40.8 +/- 5.0%, respectively). Relaxation of arteries with ACh was enhanced at 10 mo but not at 1 mo after ligation. Relaxation with sodium nitroprusside was increased in veins at 1 mo after ligation but was not altered in arteries. Morphometry revealed reduced diameters of arteries and veins without increased medial thickness. Our data suggest that the enhanced contractile responses of pulmonary vessels to histamine and 5-HT in POPV were not a result of endothelial dysfunction or of structural alterations but might be caused by as-yet-undiscovered mechanisms.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Mechanisms for the diminished neutrophil exudation to secondary inflammatory sites in infected patients with a systemic inflammatory response (sepsis).

OBJECTIVE: To determine the mechanism for the reduced polymorphonuclear neutrophil exudation to secondary inflammatory sites in critically ill patients with infection and systemic inflammatory response (sepsis). DESIGN: Prospective cohort study. SETTING: Research laboratory and integrated intensive care unit of a tertiary care university-affiliated teaching hospital. PATIENTS: Healthy subjects or critically ill patients with confirmed infection and a systemic inflammatory response (septic patients). MEASUREMENTS AND MAIN RESULTS: We found that polymorphonuclear neutrophil delivery to a secondary inflammatory site (skin window blisters) is reduced by >70% in humans with sepsis, defined as serious infection and a systemic inflammatory response compared with healthy controls. The expression of the endothelial adhesion molecules intercellular adhesion molecule-1, E-selectin and P-selectin in microvessels from skin biopsies was comparable in the two study groups. Also, CD11a and CD11b levels were equal in circulating polymorphonuclear neutrophils (PMNs) from both study groups. Both adhesion molecules were markedly and equally up-regulated during exudation. Circulating PMNs from septic patients showed marked shedding of L-selectin compared to those of healthy controls, with a corresponding increase in their plasma L-selectin levels. An increased concentration gradient between plasma and exudate fluid was found for tumor necrosis factor-alpha and interleukin-8 in septic patients, but not for C5a. The phagocytic and bactericidal capacity of septic patient circulating PMNs was higher then in healthy control patients, but these differences were lost after exudation. There were no major differences in oxidative burst or intracellular calcium flux of circulating PMNs from the two study groups. Polymorphonuclear neutrophil exudation primed both responses to different extents. CONCLUSIONS: Septic patients deliver fewer PMNs to secondary inflammatory sites. In addition, neutrophil exudation results in loss of the small priming effect for phagocytosis and bactericidal function induced by sepsis. Failure to produce a gradient to C5a and intravascular shedding of L-selectin may be responsible for this sepsis-induced reduction in neutrophil exudation to secondary inflammatory sites.

Biomarkers↗

PubMed1998

Pulmonary blastoma: case report of a patient with a 7-year remission and review of chemotherapy experience in the world literature.

BACKGROUND: Pulmonary blastoma is a rare malignant neoplasm for which there currently are no treatment guidelines. METHODS: A patient with locally advanced pulmonary blastoma is described. The treatment modality is discussed and the world literature is reviewed with respect to the use of chemotherapy. RESULTS: A 54-year-old man had a 7-year disease free survival despite subtotal resection. He was treated with adjuvant radiotherapy and combination chemotherapy. Three cycles of cisplatin and etoposide were administered. The world literature was reviewed with regard to the use of adjuvant chemotherapy in the treatment of pulmonary blastoma. CONCLUSIONS: Surgery, adjuvant radiotherapy, and combination chemotherapy with cisplatin and etoposide should be considered in the treatment of patients with this rare pulmonary neoplasm.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Differential responses of pulmonary arteries and veins to histamine and 5-HT in lung explants of guinea-pigs.

1. The mechanisms by which histamine and 5-HT differentially contract pulmonary arteries and veins are unclear. In lung explants from 26 guinea-pigs, we compared responses of pulmonary arteries and vein to histamine, 5-HT and KCI, and examined potential determinants for the differential responses. Lungs were filled with agarose, sectioned into approximately 1 mm thick slices, and vascular luminal areas measured by image analysis. 2. Histamine and 5-HT produced a concentration-dependent constriction in arteries and veins, greater in the latter. KCl constricted arteries and veins equally. 3. The histamine H1 antagonist chlorpheniramine (10(-4) M) abolished contractions to histamine; the H2 antagonist cimetidine enhanced maximal responses and sensitivity of arteries and veins to histamine, and diminished the differences between their maximal responses; the NO synthase inhibitor Nomega-nitro-L-arginine (L-NOARG) increased the maximal responses of arteries and veins, and the differences between their responses; indomethacin had no effect. 4. Contractions to 5-HT were abolished in arteries and markedly reduced in veins by the 5-HT2 antagonist ketanserin (10(-4) M); L-NOARG potentiated the maximal responses of arteries but not of veins; indomethacin increased the maximal responses of arteries but reduced them in veins. 5. By morphometry, arteries had a greater medial thickness and luminal diameter than veins. 6. The data suggest that in guinea-pigs, H2 receptors are responsible for the differential contractile responses of pulmonary arteries and veins to histamine, whereas endothelium-derived vasoactive substances are responsible for their differential contractile responses to 5-HT.

Animals↗

PubMed1997

Endothelin reactivity and receptor profile of pulmonary vessels in postobstructive pulmonary vasculopathy.

Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling and bronchial angiogenesis, collectively known as postobstructive pulmonary vasculopathy (POPV). To determine whether the reactivity of pulmonary vessels to endothelins (ET) was altered in POPV and to explore potential mechanisms, we ligated the left main pulmonary artery of 18 rats. Four weeks later, using a lung explant technique, we compared POPV lungs with controls for contractile responses of intrapulmonary vessels to ET-1 and ET-3 and for relaxant responses to ET-1 and sodium nitroprusside (SNP) after precontraction with U-46619. Morphometric measurements were made on vessels studied pharmacologically. Competition receptor binding studies with 125I-labeled ET-1 and unlabeled ET-1 and BQ-123 were performed using membrane proteins of pulmonary vessels. We found, in arteries, that contractile responses to ET-1 and ET-3 were significantly increased and that relaxant responses to ET-1 but not to SNP were reduced; in veins, only relaxation to SNP was increased. Morphometry showed that arteries and veins in POPV had reduced diameters without altered muscle thickness. Receptor binding studies showed that the proportion of ETA receptors in arteries was significantly increased in POPV (66%) vs. controls (54%). We conclude that, in POPV, the increase in reactivity to ET-1 and ET-3 is primarily related to an augmented proportion of ETA receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Differential relaxant responses of pulmonary arteries and veins in lung explants of guinea pigs.

The endothelium regulates vascular tone through release of relaxing or contracting factors, with nitric oxide (NO) being a major endothelium-derived relaxing factor. In the present study, we used a lung explant technique to determine the differential abilities and mechanisms of pulmonary arteries and veins of normal guinea pigs to relax after precontraction. Excised lungs of 15 guinea pigs were filled through the airways with 1% agarose, cut into 1-mm-thick slices, and cultured overnight. Luminal areas of vascular cross sections were measured with an image-analysis system. Vessels were precontracted with U-46619, and responses to histamine, acetylcholine (ACh), sodium nitroprusside, and papaverine were examined. We also determined the effects of N omega-nitro-L-arginine and of indomethacin on ACh-induced responses. We found that histamine relaxed arteries more than veins and that ACh relaxed only arteries. N omega-nitro-L-arginine pretreatment abolished ACh-induced relaxation of arteries and caused ACh-induced contraction of veins, whereas indomethacin markedly augmented ACh-induced relaxation of arteries (maximal relaxation: 48.5 +/- 4.7 vs. 19.2 +/- 5.1% without it) and induced a dose-dependent relaxation of veins (maximal relaxation: 17.0 +/- 4.1%). Sodium nitroprusside induced a significantly greater relaxation of arteries than veins, whereas papaverine relaxed them equally. We conclude that in guinea pigs endothelial NO-mediated relaxation is greater in pulmonary arteries than in veins and that ACh-induced NO-mediated relaxation is reduced by the simultaneous production of cyclooxygenase-derived vasoconstrictors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist.

Idiopathic pulmonary fibrosis (IPF) is characterized by an alveolitis with epithelial and endothelial damage progressing to fibrosis. Numerous mediators have been implicated in this complex process. Studies in humans have shown that endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide, is a mediator in IPF. To determine the role of ET-1 and endothelin-converting enzyme (ECE)-1 and the effect of Bosentan, an ET receptor antagonist, in an animal model of IPF, we studied three groups of rats (n = 6 each): Group 1, control, received saline; Group 2, fibrosis, received 1.5 U bleomycin intratracheally; Group 3, fibrosis-Bosentan treated, received bleomycin and Bosentan daily by gavage. After 28 d, right upper lobes were fixed for immunohistochemistry (IHC) and sections were stained with antisera to ET-1 and ECE-1 and graded semiquantitatively. Sections from left lungs were embedded in paraffin and stained for light microscopic morphometry to quantitate the fibrosis. By IHC, we found increased ET-1 immunoreactivity (ir) in airway epithelium and inflammatory cells, and ECE-1-ir in airway epithelium, type II pneumocytes and endothelial cells (p < 0.05). By morphometry, the volume fraction (Vv) of connective tissue (CT) increased and the Vv of air decreased in the fibrosis group compared with that in the control group. Bosentan reduced the Vv of CT and increased the Vv of air compared with that in the fibrosis group (p < 0.05). These results indicate that ET-1 is involved in the pathogenesis of pulmonary fibrosis in the rodent model and that blockage of its receptors reduces the fibrosis.

Animals↗

PubMed1996

Shedding of L-selectin as a mechanism for reduced polymorphonuclear neutrophil exudation in patients with the systemic inflammatory response syndrome.

BACKGROUND: It has been recently shown that patients with the systemic inflammatory response syndrome (SIRS) have reduced neutrophil exudation. OBJECTIVE: To determine whether reduced neutrophil exudation, seen in patients with SIRS, is related to differential expression of cell adhesion molecules (CAMs), by studying endothelial and neutrophil CAM expression. SETTING: A tertiary care surgical intensive care unit in a university teaching hospital. DESIGN: Twenty-six patients with SIRS were compared with 18 healthy age-matched control subjects. Blister-type skin windows were created. Exudative neutrophils were harvested, and CAM expression was quantitated by using flow cytometry. Endothelial CAM expression was studied with immunohistochemical methods by using skin biopsy specimens that were taken following subdermal injections of saline solution or tumor necrosis factor alpha. RESULTS: Despite a significant reduction in neutrophil exudation in patients, we found no difference in the baseline expression of the endothelial intercellular adhesion molecule 1, P-selectin, or E-selectin in patients vs that in control subjects. There was a significant increase in E-selectin staining in response to recombinant human tumor necrosis factor alpha in patients with SIRS, but not in control subjects. However, up-regulation of P-selectin did not occur in patients in response to recombinant human tumor necrosis factor alpha, as was observed in control subjects. L-selectin expression on circulating neutrophils was lower in patients than in control subjects, while soluble serum L-selectin levels were higher. CONCLUSIONS: Alterations in neutrophil L-selectin, not endothelial CAMs, are important in decreased neutrophil exudation. Reduced levels of neutrophil L-selectin associated with increased levels of serum L-selectin in patients with SIRS suggest premature intravascular shedding of neutrophil L-selectin. This would compromise the initial interaction between neutrophils and the endothelium, and, consequently, impede exudation.

Case-Control Studies↗

PubMed1996

Distribution of alveolar edema in ventilated and unventilated canine lung lobes.

RATIONALE AND OBJECTIVES: Pulmonary edema frequently is treated with ventilation but its effects on the distribution of edema, including gravity-dependent gradients as determined by computed tomography (CT) scanning, are unclear. METHODS: To study this, 30 to 50 mL 5% albumin in dextran were instilled in both caudal lobes of supine dogs. They were ventilated only on the left side for 1 minute (n = 4), 30 minutes (n = 6), or 60 minutes (n = 6), and the lobes excised, frozen, and imaged in a CT scanner. Regions of interest were outlined on regional CT slices and tissue from corresponding regions taken for measurements of extravascular lung water (quantity of wet lung [Qwl]/dry quantity of lung [dQl] and for histology to grade interstitial and alveolar edema. RESULTS: After ventilation for 30 and 60 minutes, the CT density of the left caudal lobes was significantly lower than the right caudal lobes (P < 0.05), with no significant differences in their Qwl/dQl. Although gravity-dependent gradients of Qwl/dQl were demonstrated, they were unaffected by ventilation. Histology showed a trend for more interstitial edema in left caudal lobes ventilated for 60 minutes compared with lobes ventilated for 1 minute (P = 0.054). CONCLUSIONS: Ventilation appears to act primarily by maintaining lung aeration and may play a minor role in alveolar fluid clearance.

Animals↗

PubMed1995

Incidence of second cancers in patients treated for Hodgkin's disease.

BACKGROUND: Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. PURPOSE: We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. METHODS: We conducted a study within a cohort that included 10,472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. RESULTS: We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0; 95% CI = 1.1-3.6), procarbazine (RR = 4.9; 95% CI = 2.6-9.1), vinblastine (RR = 1.7; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8; 95% CI = 1.9-7.4). RRs were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4; 95% CI = 1.1-5.4). CONCLUSIONS: Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. IMPLICATIONS: Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors.

Adolescent↗

PubMed1995

Different distribution of plexiform lesions in primary and secondary pulmonary hypertension.

Despite much interest in plexiform lesions, no published work compares their distribution in different types of pulmonary hypertension. Scattered reports of plexiform lesions in bronchial arteries oppose the consensus view that the lesions develop in pulmonary arteries. To compare the localization of plexiform lesions in different types of pulmonary hypertension, and to assess the role of the bronchial arteries in their formation, we examined by light microscopy lung tissue from five patients with primary plexogenic pulmonary arteriopathy (PPPA), six with pulmonary hypertension secondary to congenital cardiac malformations (CCM), and one with pulmonary hypertension complicating hepatic cirrhosis. We classified the 270 plexiform lesions observed as either preacinar or intra-acinar based on the type of pulmonary artery in which they were located, and computed the frequencies of each type of lesion within each etiologic group. We searched for lesions developing in bronchial arteries. Then, postulating that a close anatomic relationship between plexiform lesions and bronchial arteries would necessitate a clustering of the lesions near sites in the lung subserved by the bronchial circulation, we measured, for 211 of the 270 lesions previously classified, the distance from the lesion to the nearest airway and computed the mean lesion-to-airway distance in each etiologic group. The frequencies of preacinar plexiform lesions were 34% in PPPA, 67% in CCM (P < .01), and 21% in the case of cirrhosis. We found no plexiform lesions within bronchial arteries, and the mean plexiform lesion-to-airway distances were 1,680 +/- 180 microns in PPPA, 1,330 +/- 220 microns in CCM, and 2,050 +/- 1,090 microns in cirrhosis (P > .05). Our data suggest that (1) the distribution of plexiform lesions within the pulmonary arterial tree varies depending on the etiology, (2) plexiform lesions rarely if ever arise in bronchial arteries, and (3) plexiform lesions are not preferentially distributed near parts of the lung subserved by the bronchial circulation.

Adult↗

PubMed1995

Respiratory mechanics and gas exchange in postobstructive pulmonary vasculopathy.

Chronic unilateral pulmonary artery ligation induces formation of new bronchial collateral vessels in the affected lung. These vessels form precapillary anastomoses with the pulmonary circulation and the lung is perfused with arterial blood. Inspired gas is diverted to the contralateral lung to maintain the ventilation/perfusion ratio (VA/Q) and gas exchange. This study was designed to determine the mechanism responsible for this shift of ventilation, which has not previously been investigated. We studied six dogs, before and 6 months after ligation of the left main pulmonary artery. We measured pulmonary resistance (RL) and elastance (EL), minute ventilation (VE), O2 consumption (VO2) and CO2 production (VCO2) of the right and left lungs. We also examined the effect of CO2, atropine and isoproterenol on RL and EL. In the lung with ligated pulmonary artery: 1) VE was significantly reduced; 2) RL and EL were increased and were unresponsive to CO2, atropine and isoproterenol; and 3) VO2 decreased more than VCO2 and, consequently, respiratory quotient (RQ) was greater than 1. We conclude that, with chronic pulmonary artery obstruction, ventilation shifts to the contralateral lung because of an increase in RL and EL not related to airway smooth muscle tone.

Animals↗

PubMed1994

Altered mechanical properties of lung parenchyma in postobstructive pulmonary vasculopathy.

Postobstructive pulmonary vasculopathy (POPV) produced by chronic unilateral ligation of one pulmonary artery, results in perfusion of the pulmonary capillaries with systemic arterial blood. As a consequence, gas exchange occurs primarily in the contralateral nonligated lung. To determine whether the mechanical properties of the lung parenchyma are changed in POPV, we compared five dogs with chronic ligation of the left main pulmonary artery with five control dogs. Separate measurements of left and right lung airway flows, tracheal pressures, and alveolar pressures were made during mechanical ventilation at frequencies between 5 and 40 breaths/min. We calculated pulmonary elastance (EL) and pulmonary (RL), airway (Raw), and tissue (Rti) resistances. At all frequencies, dogs with POPV had higher left (ligated) EL and Rti and lower right (normal) lung Rti but similar EL compared with the respective lungs from control animals. Raw was the same in both lungs. Histology showed visceral pleura thickening and encroachment of new bronchial collaterals and lymphatics on the parenchyma of the ligated lungs. The contralateral lungs were entirely normal. We conclude that in POPV 1) there is an increase, in the ligated lung, of both EL and RL, the latter likely due to histological changes of the lung parenchyma, and 2) there is a reduction of Rti in the contralateral lung.

Airway Resistance↗

PubMed1994

Effects of pulmonary fibrosis on the distribution of edema. Computed tomographic scanning and morphology.

The pulmonary interstitium acts as an important safety factor against alveolar flooding. To test the hypothesis that in advanced fibrosis, edema is redistributed away from a less compliant interstitium to flood alveoli, we induced severe left lung fibrosis in six dogs with radiation and intratracheal bleomycin. Twenty-four months later, edema was induced by infusing 20% body weight lactated Ringer's solution over 30 min, preceded and followed by computed tomography (CT) scanning. Lower lobes were frozen, and samples were taken for extravascular lung water measurements (Qwl/dQl), regional blood volume, and light microscopic grading of interstitial and alveolar edema. The total volumes of the control and fibrotic lungs were 800 +/- 63 and 45 +/- 10 ml (SE), respectively, indicative of severe fibrosis. Before edema, the fibrotic carinal and basal slices had CT densities 3.5 and 2.2 times greater than respective control slices. After edema, the densities of all control lung slices rose 2.5 times and that of fibrotic carinal and basal slices rose 1.5 times. Edema significantly accentuated the small gravity-dependent gradient in CT density of control lungs, but it had minimal effect on this gradient in fibrotic lungs. The Qwl/dQl for control and fibrotic lower lobes were 8.7 +/- 0.8 and 6.8 +/- 0.7 g H2O/g dry lung, respectively, but the amounts of water per lung volume were similar, and there was no gravity-dependent gradient in Qwl/dQl or in regional blood contents. By light microscopy, we found significantly less interstitial and more alveolar edema in the fibrotic lobes. We conclude that in severe pulmonary fibrosis, similar amounts of water accumulate per lung volume as in controls, and that there is predominant alveolar flooding over interstitial edema. We also conclude that the gravity-dependent gradients in CT densities postedema in the control lungs are not accounted for by edema fluid or congestion, but probably by atelectasis.

Animals↗

PubMed1994

Effects of pulmonary fibrosis on the distribution of edema. Morphometric analysis.

We tested the hypothesis that in advanced pulmonary fibrosis, edema is redistributed away from the relatively noncompliant interstitium and predominantly floods alveoli. Severe left lung fibrosis was produced in six dogs with radiation and intratracheal bleomycin and, 24 mo later, hydrostatic edema was induced by infusing 20% body weight Ringer's lactate. Previously we had found, by computed tomography scanning and gravimetry, that similar amounts of water per unit volume accumulated in control and fibrotic lungs; semiquantitative light microscopic grading showed less interstitial and more alveolar edema in the fibrotic lungs. In the present study, we extended these observations with detailed morphometric assessment of volume fractions and absolute volumes of the pulmonary compartments, and we examined the lungs with electron microscopy. We found a twofold rise in the volume fractions of connective tissue and alveolar edema (p < 0.05) and a 50% reduction of air and of interstitial edema in fibrotic lobes (p < 0.05). There was a marked reduction in the absolute volume of edema, paralleling the reduction in lung volume in fibrosis, and minimal gravity-dependent edema gradients in both control and fibrotic lungs. In the latter, evidenced by electron microscopy, the interstitial edema was randomly distributed, whereas in the control lungs, it was found primarily around extra-alveolar vessels and airways, not in the alveolo-capillary septa. We conclude that fibrosis profoundly affects the distribution of edema in the lung.

Animals↗

PubMed1993

Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis.

The vasoconstrictor and mitogenic peptide endothelin-1 (ET-1) is believed to play a part in fibrosis and collagen production. We examined expression of ET-1 in lung tissue from 52 patients with interstitial lung fibrosis, of whom 45 had cryptogenic fibrosing alveolitis (CFA), 10 had CFA and concomitant pulmonary hypertension, and 7 had non-specific focal fibrosis. 17 normal unused donor lungs were studied as controls. Immunohistochemistry and in-situ hybridisation were done with polyclonal antisera to ET-1 and its precursor big ET-1, and complementary RNA probes for preproET-1. Normal lung tissue and that from patients with focal fibrosis expressed very little ET-1. By contrast, there was striking expression of ET-1 in lung tissue from patients with CFA. Immunostains for ET-1 and big ET-1 and expression of ET-1 mRNA were most prominent in airway epithelium and type II pneumocytes, particularly those lining areas of young granulation tissue. ET-1-like immunoreactivity and mRNA were also present in pulmonary vascular endothelial cells, particularly in specimens from patients with pulmonary hypertension. In all patients, there was a significant correlation between ET-1-like immunoreactivity and histological parameters of disease activity (r = 0.78, 95% CI 0.65-0.87, p < 0.001). These findings suggest a possible role for cell-specific expression of ET-1 in the pathogenesis of CFA and associated pulmonary hypertension.

Biomarkers↗