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J H Sisson

Publications and source records attributed to J H Sisson.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis.

Cigarette smoking is the most clearly recognized cause of pulmonary emphysema. Since loss of lung tissue, which characterizes emphysema, represents a balance between injury and repair, we hypothesized that cigarette smoke might contribute to the development of emphysema by inhibiting fibroblast proliferation and migration. To evaluate this, we examined the effect of cigarette smoke extract (CSE) on the proliferation and migration of human lung fibroblasts in vitro. CSE inhibited fibroblast proliferation and migration at noncytotoxic concentrations. When CSE was treated to remove volatile components, it showed less inhibitory activity on fibroblast proliferation. Therefore, we also examined acrolein and acetaldehyde, which are volatile components of cigarette smoke, Micromolar concentrations of acrolein and millimolar concentrations of acetaldehyde induced significant inhibition of fibroblast proliferation. In contrast, removal of volatile components did not eliminate the inhibitory activity of CSE for fibroblast migration, although acetaldehyde and acrolein alone were also capable of inhibiting chemotaxis. Cigarette smoke-induced inhibition of fibroblast proliferation and migration may impair lung repair following lung injury, and may thus contribute to the development of pulmonary emphysema.

Acetaldehyde↗
PubMed1995

Immunological functions of the pulmonary epithelium.

The mature pulmonary epithelium forms a continuous lining to the airspace. Recent data suggest that this specialized epithelium may also contribute to host defence via interactions with inflammatory cells. Pulmonary epithelial cells can serve as part of the local immune system, providing structures and functions crucial for the maintenance of normal pulmonary function. This article will briefly review the morphology and development of the pulmonary epithelial cells, their function with regard to host defence, alterations of the pulmonary epithelium associated with airway diseases, and potential therapeutic implications for the treatment of respiratory diseases.

Epithelium↗
PubMed1995

Effects of guaifenesin on nasal mucociliary clearance and ciliary beat frequency in healthy volunteers.

STUDY OBJECTIVE: Mucociliary clearance is an important host defense function of the upper respiratory tract that requires the coordinated beating of cilia and results in the transport of mucus to the oropharynx. Guaifenesin is a commonly prescribed drug that is reported to improve the clearance of respiratory secretions. We hypothesized that guaifenesin increases nasal mucociliary clearance related to increases in ciliary beat frequency (CBF) and that a direct relationship exists between nasal CBF and nasal mucociliary clearance. DESIGN: Double-blind placebo-controlled crossover study. PARTICIPANTS: Ten healthy volunteers with a previous history of sinus disease. INTERVENTIONS: Subjects received guaifenesin or placebo on days 1 to 7 or days 14 to 21. MEASUREMENTS AND RESULTS: In vivo saccharine transit time (STT) was measured by noting the time in minutes required for the subject to taste a saccharin particle placed on the inferior turbinate of the naris. The CBF was determined by video microscopy on ten separate groups of beating ciliated nasal mucosal cells obtained by brushing immediately after each STT determination. We found that there was no significant change between the guaifenesin-or placebo-treated groups from baseline values of STT (p = 0.94) or CBF (p = 0.46). Regression analysis demonstrated no relationship between STT and CBF for repeated measures within subjects (mean r2 = 0.18; mean p = 0.66) and between STT and CBF when all paired measurements were combined across subjects (r2 = 0.47; p = 0.46). CONCLUSION: We conclude that guaifenesin exerts no measurable effect on in vivo nasal mucociliary clearance or ex vivo nasal ciliary motility in healthy volunteers with previous sinus disease. In addition, there appears to be no relationship between nasal STT measured in vivo and CBF measured ex vivo. The lack of correlation is most likely due to variations in CBF related to sampling artifacts introduced by the nasal brushing process.

Cilia↗
PubMed1994

Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. University of Nebraska Medical Center Bone Marrow Transplant Group.

BACKGROUND: Diffuse alveolar hemorrhage is a frequent complication of treating malignancies with high-dose chemotherapy and bone marrow transplantation and is associated with very high mortality. This disorder's association with pulmonary inflammation, its coincidence with marrow recovery, and the usefulness of corticosteroids for treating other pulmonary hemorrhage syndromes provided the rationale for this study. METHODS: We retrospectively studied 65 episodes of diffuse alveolar hemorrhage that has occurred in 63 of 603 consecutively treated patients who had undergone high-dose chemotherapy with bone marrow transplantation. Patients were divided into three groups according to the therapy they had received for diffuse alveolar hemorrhage: supportive therapy alone (n = 12); low-dose corticosteroids (30 mg or less of methylprednisolone or its equivalent; n = 10); and high-dose corticosteroids (more than 30 mg methylprednisolone or its equivalent; n = 43). The primary outcome measures were overall survival and survival to hospital discharge, occurrence of respiratory failure requiring intubation, and development of infections subsequent to the diagnosis of diffuse alveolar hemorrhage. RESULTS: Overall survival at the end of the follow-up period was significantly higher for the high-dose corticosteroid group compared with the supportive therapy group (P = 0.005); however, treatment with low-dose steroids did not increase survival over supportive therapy alone (P = 0.198). In addition, survival to discharge was significantly increased for the high-dose group compared with the other two groups combined (33% versus 9.1%, P = 0.038). Respiratory failure after the diagnosis of diffuse alveolar hemorrhage developed in only 12 of the 22 unintubated patients in the high-dose group compared with 9 of the 10 initially unintubated patients in the other two groups (P = 0.056). Although the incidence of infections was high (40%) subsequent to diffuse alveolar hemorrhage, neither high-dose nor low-dose corticosteroid treatment significantly increased the risk of infections (P > 0.4, all comparisons). CONCLUSIONS: In this study, high-dose corticosteroid therapy for diffuse alveolar hemorrhage related to bone marrow transplantation was associated with improved total survival and survival to hospital discharge, and decreased development of respiratory failure in these patients. These results suggest the therapy is beneficial, and further prospective studies are warranted to verify the effectiveness of the treatment.

Adult↗
PubMed1994

Vapor phase exposure to acetaldehyde generated from ethanol inhibits bovine bronchial epithelial cell ciliary motility.

Acetaldehyde is a toxic product of the oxidation of ethanol and is known to induce slowing of ciliary motility in airway epithelium. Alcohol ingestion results in high exhaled breath concentrations of ethanol where lung microsomes and upper airway bacterial flora are capable of metabolizing it to acetaldehyde. Because acetaldehyde is very volatile, we hypothesized that the production and release of acetaldehyde vapor into the airway may result in ciliary slowing or ciliastasis. To test this hypothesis, ciliated bovine bronchial airway epithelial cells were maintained on collagen-coated dishes for 48 hr before coincubation with a separate dish containing control or test mixtures. In this arrangement, the ciliated cells were exposed only to the volatile components of the separate dish. The separate dish contained ethanol, acetaldehyde, or an acetaldehyde-generating system (AGS) that consisted of ethanol + glucose + glucose oxidase + catalase. This mixture was placed next to the ciliated cells within in a transparent sealed chamber. Ciliary motility was recorded at room temperature by video microscopy, and ciliary beat frequency was determined using computerized frequency spectrum analysis. Exposure to the AGS resulted in time- and concentration-dependent ciliary slowing with complete ciliastasis, with as low as 20 mM ethanol in the AGS. Direct vapor phase exposure to acetaldehyde alone served as a positive control and also resulted in time-dependent ciliary slowing with complete ciliastasis reached by 4 hr. The AGS-induced ciliastasis was reached 2 hr later than with acetaldehyde alone. When cells were pretreated with cyanamide, which is known to block acetaldehyde dehydrogenase, the time to ciliastasis was decreased by 10-30 min compared with untreated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1994

Smoke and viral infection cause cilia loss detectable by bronchoalveolar lavage cytology and dynein ELISA.

The purpose of this study was to quantitate cilia loss following airway epithelial cell injury. Two models of airway injury were used: (1) Ex vivo acute cigarette smoke exposure model: Bovine lungs, obtained directly after slaughter, were ventilated with air or cigarette smoke for 5 min followed immediately by bronchoalveolar lavage (BAL). The bronchi were examined histologically and bronchial and alveolar fractions of BAL fluid were examined for cell counts, cell differentials, and cilia dynein concentrations using a specific 13S dynein ELISA. Smoke exposure resulted in a marked loss of ciliated cells from the bronchial luminal surface (2,364 +/- 351 versus 11,090 +/- 542 ciliated cells/mm2; p = 0.0001), a comparable increase in ciliated cells in the bronchial BAL fraction (0.90 x 10(6) cells/mm3 versus 0.15 x 10(6) cells/mm3; p = 0.0003) and a significant increase in bronchial fluid dynein concentrations (24.5 +/- 6.0 micrograms/ml versus 8.9 +/- 2.2 micrograms/ml; p = 0.03) compared with that in air-exposed lungs. The dynein concentrations strongly correlated with the absolute number of ciliated cells recovered in the bronchial lavage (r = 0.80; p < 0.0001). (2) In vivo viral infection model: Healthy cattle underwent bronchoscopy 3 days before and 7 days after inoculation with bovine respiratory syncytial virus (BRSV). BAL fluid was examined as in the first model. Following BRSV inoculation, airway exfoliation of ciliated cells and squamous metaplasia were observed histologically, bronchial ciliated cell counts doubled (0.011 +/- 0.003 x 10(6) cells/mm3 versus 0.026 +/- 0.006 x 10(6) cells/mm3; p = 0.002) and bronchial dynein concentrations increased threefold (2.2 +/- 1.0 micrograms/ml versus 7.2 +/- 1.9 micrograms/ml; p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Impairment of nasal mucociliary clearance during bone marrow transplantation. University of Nebraska Medical Center bone Marrow Transplantation Pulmonary Study Group.

Transient mucositis occurs in almost all patients receiving bone marrow transplantation (BMT) but it is not known whether airway mucociliary transport is impaired during this period. We hypothesized that the preparative regimen associated with BMT impairs mucociliary clearance during the peri-transplant period. To test this hypothesis we determined nasal saccharine transit time (STT) and a mucositis score daily throughout the peri-transplant hospitalization in 13 patients receiving BMT. STT was prolonged in all patients at some time during the peri-transplant period and mucociliary clearance was ineffective in 12 of 13 patients for an average of 22% of the days. STT was most prolonged (about 155% of baseline) in the 2 week period following marrow infusion and correlated with the appearance of mucositis. STT returned to baseline values within 30 days after marrow infusion in all but one patient. These findings demonstrate that nasal mucociliary clearance is significantly impaired in most patients during BMT, if only temporarily. This decrease in local airway host defense may explain, in part, the increased risk of upper respiratory infections that these patients experience.

Adult↗
PubMed1993

Modulation of airway epithelial cell ciliary beat frequency by nitric oxide.

NOS activity has been recently described in airway epithelial cells. Because these cells are often ciliated we hypothesized that NO modulates airway ciliary beating. CBF was measured in cultured BBECs using video microscopy. L-NMMA, a NOS inhibitor, caused a 40% decrease in CBF following pre-stimulation with isoproterenol (8.5 +/- 0.3 Hz vs 14.6 +/- 0.2 Hz; p < 0.0001) which lasted approximately 60 minutes. Similar attenuation in CBF after isoproterenol pre-treatment was observed with another NOS inhibitor, L-NAME. NOS inhibitor-induced CBF slowing was also observed when cells were pre-stimulated with either bradykinin or substance P and was completely reversed by L-arginine or SNP but not by D-arginine. These observations demonstrate a novel NO-dependent mechanism that upregulates ciliary motility in response to stimulation.

Amino Acid Oxidoreductases↗
PubMed1993

The bronchitis index. A semiquantitative visual scale for the assessment of airways inflammation.

Flexible fiberoptic bronchoscopy has been proven to be an effective tool for the assessment and characterization of airway inflammation. Visual inspection of airways affected by chronic bronchitis discloses an abnormal appearance characterized by erythema, edema, secretions, and friability. It was hypothesized that the visual appearance of airway inflammation could be assessed in a semiquantitative manner. A bronchitis index (BI) was developed that scores the visual appearance of airways according to the presence or absence of abnormal edema, erythema, secretions, and friability (0 = normal, 3 = remarkably abnormal). The BI was determined in three study groups: 86 subjects with chronic bronchitis, 15 subjects who smoked cigarettes, but did not have chronic bronchitis, and 25 normal, nonsmoking control subjects. The reproducibility of the BI was determined by comparing the results from pairs of two independent observers assessing 249 subjects undergoing fiberoptic bronchoscopy under various investigative protocols. In total, nine investigators scored the airways. For the three observer pairs with more than six observations, there were no differences noted in the BI (p = 0.43, 0.67, 0.82). To control for the effect of cough upon the BI, lidocaine usage was recorded. No correlation was found between lidocaine usage and BI. As previously noted for a smaller group of subjects, the BI was found to be elevated in those with chronic bronchitis (13.2 +/- 0.53) compared with both asymptomatic smokers (8.5 +/- 0.89, p < 0.0005) and normal volunteers (2.3 +/- 0.55, p < 0.0001); the latter two groups also differed significantly (p < 0.0001). The BI was also found to correlate significantly with bronchial sample lavage fluid neutrophil content in lavage fluid obtained after determination of the BI and with cigarette smoking as quantitated by pack years. Conversely, the BI correlated negatively with the spirometric measures of airway obstruction, FEV1, FEV1/FVC, FEV25-75, and FEFmax. Thus, the BI appears to be a reproducible, semiquantitative assessment of the visual appearance of airway inflammation. It may be a useful bronchoscopic adjunct for the assessment of airway inflammation in clinical investigations.

Adult↗
PubMed1993

General vs local anesthesia. Effect on bronchoalveolar lavage findings.

Bronchoalveolar lavage (BAL) can be performed with the patient undergoing either local or general anesthesia (GA). This study investigates whether the type of anesthesia affects BAL fluid and cell recovery. Eighty patients, were selected for study. Fluid recoveries were significantly less in the GA group for both the bronchial and alveolar lavages. The differences were confirmed for BAL fluid recovery in a subsequent group of 120 unselected patients. Bronchoscope size did not appear to affect recovery, nor did anesthesia time; BAL fluid recovery from patients with respiratory failure who were intubated and mechanically ventilated was similar to that in the GA group, suggesting that lower recovery rates may be due to mechanical ventilation. The BAL fluid cell counts were related to fluid recovery, but airway neutrophils represented a higher percentage of BAL lavage fluid cells in the GA lavages, independent of differences in the volume of lavage fluid recovered.

Adult↗
PubMed1992

Pulmonary complications of transplantation.

Improved immunosuppressive regimens, advances in surgical proficiency and techniques, and improved supportive medical care have translated into dramatic increases in graft survival in organ transplantation and in patient outcome in bone marrow transplantation. Though effective immunosuppression has also led to an increase in infectious complications, several recent advances, including the development of effective surveillance protocols and antiviral therapy and the use of prophylactic antibiotics, appear to have made a significant positive impact on the management of infections and survival of transplant recipients. In addition, a clearer understanding of noninfectious pulmonary complications, such as bronchiolitis obliterans, and continued improvement in techniques for evaluating a host of posttransplant pulmonary disorders will likely further enhance posttransplant therapy and survival.

Bronchiolitis Obliterans↗
PubMed1992

Airway inflammation predicts diffuse alveolar hemorrhage during bone marrow transplantation in patients with Hodgkin disease.

We determined risk factors present in patients with Hodgkin disease that predicted the development of diffuse alveolar hemorrhage syndrome (DAH) during autologous bone marrow transplantation (BMT). One hundred twenty-three patients with Hodgkin disease prospectively underwent bronchoscopy with bronchoalveolar lavage (BAL) before receiving BMT. The bronchitis index (BI) of the airways and bronchial and alveolar cell counts and differentials were determined in all patients and compared with 20 normal nonsmoking volunteers. Logistic regression analysis was used to determine factors that predicted for the development of DAH. Visual evidence of bronchial injury was observed regardless of smoking history (BI = 7.8 +/- 0.5 for BMT versus 2.3 +/- 0.5 for volunteers, p = 0.001). BMT patients who developed DAH (n = 14) had significantly greater numbers of bronchial neutrophils and eosinophils compared with DAH-negative (n = 109) patients (bronchial polymorphonuclear leukocytes (PMN), 33 +/- 7% versus 14 +/- 2%, p = 0.006; bronchial eosinophils, 0.9 +/- 0.3% versus 0.4% +/- 0.07%, p = 0.02). Logistic regression analysis revealed that the presence of bronchial PMN > 20% or bronchial eosinophils > zero% were predictive of DAH (p = 0.005 and 0.05, respectively). When both predictors were positive, the rate of DAH was 10 times greater than when both predictors were negative (43% versus 4% DAH occurrence). Survival was also significantly reduced when these predictors were positive. This study demonstrates that bronchial inflammation is present with or without intraluminal inflammatory cells in the majority of patients with Hodgkin disease before BMT. The subgroup of these patients with increased bronchial inflammatory cells are at greatly increased risk for development of DAH and death.

Academic Medical Centers↗
PubMed1992

Transforming growth factor-beta stimulates the expression of desmosomal proteins in bronchial epithelial cells.

Transforming growth factor-beta 1 (TGF-beta 1) has been shown to induce squamous differentiation of cultured airway epithelial cells. It has also been shown to increase expression of matrix proteins and integrin receptors in cell culture of these and other cells. However, it is unknown if TGF-beta 1 affects expression of genes encoding intercellular junctional proteins. Therefore, we have investigated the effect of TGF-beta 1 on the expression of proteins and mRNAs for desmoplakins (DPs) I and II, desmosomal plaque proteins. Fibronectin, known to be induced by TGF-beta 1 was used as a positive control and tubulin as a negative control. Twenty-four hours after TGF-beta 1 stimulation, DP I and II mRNA levels assessed by Northern blotting analysis had increased significantly (DP I mRNA, 1.8-fold, P less than 0.05; DP II mRNA, 2.4-fold, P less than 0.04), thereby indicating pretranslational regulation of DP expression. By comparison, mRNA for fibronectin increased 8.1-fold whereas mRNA for tubulin was unchanged. Immunofluorescence using the monoclonal anti-DP I and II antibodies revealed dramatic increased expression of punctate DP structures after exposure to TGF-beta 1. Immunoblot analyses with polyclonal anti-DP I antibodies showed increased levels of both DP I (250 kD) and DP II (215 kD), with the DP I increase being more pronounced (DP I, 2.5-fold; DP II, 1.4-fold at 48 h relative to controls), suggesting translational regulation by TGF-beta 1. This study therefore demonstrates the ability of TGF-beta 1 to alter cellular phenotype by altering expression of proteins involved in intercellular junctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Acetaldehyde-mediated cilia dysfunction in bovine bronchial epithelial cells.

Acetaldehyde, which is present in significant concentrations in cigarette smoke and is elevated during alcohol ingestion, has been demonstrated to impair mucociliary clearance of the lung. Acetaldehyde is also known to impair protein function through the formation of acetaldehyde-protein adducts. We hypothesized that acetaldehyde impairs bronchial epithelial cilia motion by inhibiting cilia dynein adenosinetriphosphatase (ATPase) activity through the formation of acetaldehyde adducts with cilia proteins. Acetaldehyde induced concentration- and time-dependent slowing of cilia beating and cilia-derived dynein ATPase activity in primary cultures and isolated axonemes of bovine airway epithelial cells. Cilia slowing and ATPase inhibitory effects were also observed with related aldehydes but not with ethanol. Acetaldehyde binding, assessed by gel electrophoresis using [14C] acetaldehyde, was demonstrated to occur with the dynein heavy chains and with tubulin and closely paralleled ATPase inhibition. We conclude that acetaldehyde directly impairs bronchial cilia function causing slowing of cilia beating, inhibits cilia dynein ATPase activity, and binds to cilia proteins critical for motion including dynein and tubulin. These data suggest that acetaldehyde-induced cilia dysfunction may be related to direct cilia ATPase inactivation and adduct formation with cilia dynein and tubulin. This may be an important mechanism by which airway host defenses are impaired in clinical settings where acetaldehyde exposure occurs, e.g., with cigarette smoking and alcohol ingestion.

Acetaldehyde↗
PubMed1987

Production of platelet-activating factor by stimulated human polymorphonuclear leukocytes. Correlation of synthesis with release, functional events, and leukotriene B4 metabolism.

Platelet-activating factor (PAF) is a phospholipid mediator of inflammation that is synthesized by several human cell types including polymorphonuclear leukocytes (PMN). We examined the synthesis and release of PAF by stimulated human PMN under several conditions, assayed by the incorporation of [3H]acetate into PAF and by bioassay. PAF synthesis was induced by calcium ionophore A23187 (IoA), opsonized zymosan (OpsZ), and N-formyl-methionyl-leucyl-phenylalanine (FMLP) with the relative order of potency IoA much greater than OpsZ greater than FMLP. A variety of other agonists, including phorbol myristate acetate, an activator of protein kinase C and of PMN functional responses, did not stimulate PAF synthesis. PAF synthesis by PMN in response to IoA, OpsZ, and FMLP was concentration- and time-dependent but release of the phospholipid was not: little PAF (1 to 10%) was released from PMN in suspension regardless of the total amount produced, the agonist, its concentration, the time of incubation, or the concentration of extracellular albumin. This was also the case with functionally altered neutrophils that had been "primed" with cytochalasin B or lipopolysaccharide or that had adhered to surfaces. PAF synthesis was tightly coupled with leukotriene B4 production by adherent PMN as well as by neutrophils in suspension, supporting the hypothesis that the two lipid autacoids may be derived from a common precursor. However, PAF synthesis could be dissociated from aggregation and surface adhesion, indicating that it is not absolutely required for these responses of activated PMN. The total amount of PAF that accumulated, but not the percentage that was released, was altered in adherent PMN compared to cells in suspension. These experiments demonstrate that PAF production and its subsequent processing by human neutrophils are highly regulated events. PAF synthesis is associated with PMN activation, but it is not a requisite for early adhesive responses of neutrophils. Because little of the PAF produced by stimulated PMN is released from the cells, it appears that PAF has an intracellular role in PMN function and/or that it may have novel intercellular effects that do not require release into the fluid phase.

Calcimycin↗