This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. Elastases release growth factors from extracellular matrices and interstitial cell surfaces, which can regulate the repair process. Brief treatment of matrix-laden rat pulmonary fibroblast cultures with porcine pancreatic elastase results in the release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) together with previously identified fibroblast growth factor-2 (FGF-2). In matrix-laden pulmonary fibroblasts, HB-EGF and two other EGF family ligands, i.e. EGF and transforming growth factor a, significantly down-regulate elastin mRNA via activation of the EGF receptor. HB-EGF treatment initiates a signaling pathway involving extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation and subsequent nuclear accumulation of Fra-1, which leads to inhibition of elastin gene transcription. Co-addition of HB-EGF and FGF-2 results in an additive inhibitory effect on elastin mRNA levels. The increased effect of HB-EGF and FGF-2 on elastin mRNA is associated with their additive actions on ERK1/2 activation, c-fos mRNA induction and Fra-1 nuclear accumulation. Further, HB-EGF induces FGF-2 mRNA and protein, suggesting a potential role of endogenous FGF-2 in mediating HB-EGF-dependent responses. Cell migration represents an important component of injury/repair. A chemotactic activity for pulmonary fibroblasts was identified within the elastase-released products. Characterization of this activity indicates that elastase-released FGF-2 is a major chemotactic component of the elastase digest. Furthermore, our data strongly suggest that the elastase digest contains another component(s) that potentiates the chemotactic activity of FGF-2. Collectively, the present study supports a model in which elastase-released growth factors and other components act in concert to regulate elastin gene expression and cell migration in injury/repair situations. / 2031-01-01

Thesis (M.D.)--Boston University.

No description available.

Monocrotaline is a pyrrolizidine alkaloid found in plants implicated in livestock and human poisoning. Laboratory rats given monocrotaline develop pulmonary hypertension and right heart hypertrophy in the weeks following administration of the chemical. Lung weight increases and right heart hypertrophy correlate with increased pulmonary artery pressure. Rats which consumed monocrotaline drinking water (20 mg/l) for only 4 days developed significant increases in lung and heart weights 14 days after exposure began. This exposure was equivalent to a dose of 15 mg/kg. Other treatment combinations of time (0-10 days exposure) and monocrotaline concentration (5-60 mg/l in drinking water) were tested. The accumulative dose calculated for each of the treatment combinations which produced toxicity was in the range of 15 to 20 mg/kg. Monocrotaline injury appears to be cumulative, but organ weight increases reverse once exposure is stopped. As pulmonary hypertension develops and pulmonary arteries hypertrophy, the force with which isolated pulmonary artery segments contract decreases. This is a loss of efficacy rather than potency to the contracting agents KCl, norepinephrine, and 5-hydroxytryptamine. Relaxation of arteries under conditions of potassium-return (a measure of Na⁺/K⁺ ATPase activity) was also altered by monocrotaline treatment. In vivo monocrotaline treatment had little effect on the force of K⁺-return relaxation. However, the rate at which arteries relaxed was significantly decreased following 4 days ingestion of monocrotaline drinking water (20 mg/l). In vitro ouabain treatment and endothelial injury also decreased the rate of K⁺-return relaxation. Another Na⁺/K⁺ ATPase activity, ⁸⁶Rb⁺ uptake, was decreased following monocrotaline treatment only when 5-hydroxytryptamine was present and only uptake associated with the endothelium was affected. These studies utilized a very low exposure to monocrotaline (4 days ingestion of 20 mg/l monocrotaline drinking water or 15 mg/kg) to produce toxicity in rats. Monocrotaline-induced toxicity measured 20 days after treatment included right heart and lung hypertrophy and decreased contractions of isolated pulmonary arteries. Monocrotaline treatment decreased the rate of Na⁺/K⁺ ATPase-dependent relaxation of isolated pulmonary arteries 4 days after treatment began.

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xi, 145 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 134-142).

Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains vii, 141 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

Previous studies have showed an association between emotional distress and decreased physical functioning in patients with pulmonary hypertension (PH); however, none controlled for demographic and disease characteristics. This study investigates the independent association of depressive symptoms with physical functioning after controlling for both demographic and disease characteristics. Fifty-two patients, mean age 61 (SD = 14) years, undergoing cardiac catheterization, completed self-report questionnaires of depressive symptoms and physical functioning. Results showed that depressive symptoms (beta = -.28, p < .05) accounted for a statistically significant 8% of incremental variance in physical functioning over and above the variance explained by demographic and disease characteristics. The direction of effects cannot be determined because of the cross-sectional design. As such, the association of depressive symptoms with physical functioning in PH patients indicates the need for longitudinal research regarding the possible effect of depression on disease outcomes in this population.

When spontaneous breathing (SB) is allowed during mechanical ventilation (MV), atelectatic lung areas are recruited and oxygenation improves thereby. Whether unsupported SB at its natural pattern (without PEEP and at low pressure/small tidal volume) equally recruits and improves oxygenation, and if so by which mechanism, has not been studied. A porcine lung collapse model was designed to study this question. The cardiac output dependency of the pulmonary shunt was investigated with healthy lungs and with major shunt (during one-lung ventilation) and with SB, MV and continuous positive airway pressure (CPAP). The hypoxic pulmonary vasoconstriction (HPV) was blocked with sodium nitroprusside (SNP) to see whether HPV is the only mechanism available for ventilation/perfusion (VA/Q) matching during MV and SB. In all experiments, respiratory rate and tidal volume during MV were matched to SB. Oxygenation was assessed by serial blood gas measurements, recruitment by thoracic CTs; pulmonary shunt was assessed by multiple inert gas elimination or venous admixture. SB attained better oxygenation and lower pulmonary shunt compared with MV, although it did not recruit collapsed lung. Pulmonary shunt did not correlate with cardiac output during SB, whereas a correlation was found during MV and CPAP. With blocked HPV, pulmonary shunt was considerably lower during SB than MV. In conclusion, SB improves VA/Q matching as compared with MV, even when no recruitment occurs. In contrast to MV and CPAP, cardiac output has no major effect on pulmonary shunt during SB. The improved VA/Q matching during SB despite a blocked HPV might indicate the presence of a SB-specific mechanism that improves pulmonary blood flow redistribution towards ventilated lung regions independent of or supplementary to HPV.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [195]-230).