Graduation Date

Summer 8-9-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Integrative Physiology & Molecular Medicine

First Advisor

Dr. Han-Jun Wang

Abstract

Acute lung injury (ALI) triggers inflammation that disrupts the normal alveolar-capillary endothelial barrier, impairing gas exchange and causing hypoxemia, which reflexively increases respiration. An elevated respiratory rate (fR) usually develops within hours to days following ALI. This acute respiratory failure disorder affects approximately 200,000 new cases annually in the US and accounts for 10% of ICU admissions, with high morbidity and mortality. The neural mechanisms underlying respiratory dysfunction post-ALI are not fully understood. My doctoral dissertation aimed to investigate the mediators of abnormal ventilation during ALI. Systemic hypoxia stimulates the carotid body (CB) chemoreflex, a crucial protective reflex that maintains oxygen homeostasis. This dissertation explores 1) chemoreflex changes post-ALI during early and recovery phases, examining both moderate (low-dose bleomycin, 1.25 mg/kg) and severe (high-dose bleomycin, 2.5 mg/kg) ALI in male rats, 2) sex-based differences in ALI, 3) the role of the superior cervical ganglion (SCG) in chronic chemoreflex sensitization, and 4) the potential neuroprotective effects of ProGel-Dex on chemoreflex sensitivity post-ALI.

In the initial study, chemoreflex responses to hypoxia and normoxic-hypercapnia were assessed. Moderate ALI rats displayed activated but not significantly different chemoreflex responses compared to controls at week 1 (W1) post-ALI. Conversely, severe ALI rats exhibited a blunted response. A 90% hyperoxia challenge ruled out a "ceiling effect," as no changes in resting fR were observed. Both ALI severities resulted in sensitized chemoreflex activation at Week 4 (W4) post-ALI.

The second study focused on sex differences post-ALI, revealing that male rats had a more pronounced increase in resting fR during the ‘early’ phase of ALI. However, chemoreflex sensitivity during the ‘recovery’ phase of ALI (W4 post-ALI) was consistent across the sexes. Subsequent studies were conducted on male rats.

The third study explored the SCG's involvement in chronic chemoreflex sensitization. Bilateral SCG ganglionectomy before bleomycin administration did not alter resting ventilatory parameters but significantly reduced chemoreflex activation in ganglionectomy bleo rats compared to sham-operated bleo rats.

The final study investigated the effects of ProGel-Dex (10µl/CB), 20 w/v%), a novel thermoresponsive drug on chronic chemoreflex sensitivity post-ALI. Although a single, local injection of ProGel-Dex did not significantly impact chemoreflex sensitization during the ‘recovery’ phase of ALI (W4 post-ALI), it effectively reduced the increase in resting fR at the ‘early’ phase of ALI (W1 post-ALI).

Collectively, these studies elucidate the impact of ALI on chemoreflex function, highlight sex-based differences in ALI, and identify SCG involvement in chronic sensitization post-ALI. They also explore therapeutic interventions, such as ProGel-Dex, aiming to improve the quality of life for ALI patients.

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Available for download on Thursday, July 23, 2026

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