Research

Dr. Teodorescu’s translational research program builds on the long-term tradition in Sleep/Pulmonary research established by the late Dr. James B. Skatrud and by Dr. Jerome A. Dempsey at the William S. Middleton Memorial VA Hospital. The focus of the program is to develop effective strategies for treating chronic lung disease (CLD) (such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis) by targeting its interaction with sleep and sleep-breathing disorders, such as obstructive sleep apnea (OSA). This earlier interest stemmed from the fact that little was known about what, now, we’ve learned to be a bidirectional relationship between CLD and OSA (ie, the lower and upper airways are truly “united”): patients with CLD are more prone for developing sleep apnea, which in turn exacerbates their lung disease. In adults, these relationships are most relevant to the elderly.

Current work centers on translation of earlier clinical findings, probing mechanisms bi-directionally linking OSA with obstructive lung diseases (OLD) (asthma and COPD) and/or pulmonary fibrosis. Concurrent human and animal studies are ongoing examining:

OSA pathogenesis in OLD:

Our studies have found that OLD may predispose to development of OSA and that it is a unique set of characteristics related to OLD which may be the culprit. These include features of the OLD itself and use of corticosteroid medications.

Pathways currently being investigated probe the dynamic physiology between the lower and upper airway during sleep, and the role of asthma-related inflammation in modulating the upper airway function. Additionally, the effects of inhaled corticosteroids on the upper airway structure and function during sleep and wakefulness are being investigated. A recent small experimental study tested short-term effects of inhaled corticosteroid on the upper airway in patients with asthma, and suggested that the individual responses are dependent upon baseline characteristics, with older age, male gender and worse asthma control predicting deterioration in the upper airway function during sleep.

Current human studies are expanding upon these initial findings and their implications on sleep-disordered breathing severity. Methods employed include nighttime physiologic measurements (airway resistance, upper airway critical closing pressure) following experimental interventions. Tongue function changes during wakefulness, as well as its fat content and in the other surrounding upper airway structures using magnetic resonance imaging, are monitored in response to these treatments. Our human work is paralleled by animal experiments assessing the effects of corticosteroid effects on tongue muscle structure and function and that of allergic-induced inflammation on breathing control, and how aging is interacting with these processes.

Effects of OSA on CLD:

We and others have shown that patients with overlap of OSA, and OLD or Idiopathic Pulmonary Fibrosis (IPF) have worse morbidity and mortality. Conversely, treatment for OSA with continuous positive airway pressure (CPAP) improves lung disease control and mortality.

Ongoing human work focuses on characterizing clinical outcomes as well as mechanistic links with the lower airway dysfunction and inflammation in OSA/ asthma phenotype. Methods include detailed sleep and pulmonary physiology studies as well as airway exhaled gasses, condensate and sputum sampling.

In rodents, we are modeling these relationships making use of chronic intermittent hypoxia (CIH)—one hallmark feature on OSA—and testing its effects on the lower airway and lung tissue. Two models are being characterized, of CIH effects:

  1. during allergen-induced inflammation. Initial work in this model finds CIH induces:
    1. airflow limitation, independent of allergen;
    2. change towards a monocyte-predominant, Th-1 airway inflammation;
    3. increased collagen deposition in more proximal airways and increased matrix degradation in the distal airways and parenchyma.
    These changes are concerning, since none are responsive to current standard therapies for asthma. Thus, current efforts delve into their underpinnings, to identify therapeutic targets that could be taken back to humans;
  2. on lung fibrosis during bleomycin-induced injury. In our early work in this model using a low dose of bleomycin exposure, we find that CIH led to:
    1. upregulation of bleomycyn-induced total lung collagen content; associated with
    2. impaired gas exchange.

In our animal work, we employ advanced pulmonary physiologic methods, such as plethysmography in awake, behaving rodents, airflow and volume measurements in anesthetized rats, as well as assessment of airway resistance, lung tissue impedance and elastance using the Flexi Vent system (Scireq). Additionally, we use cytologic and biochemical analyses of brochoalveolar fluid and lung tissues, including flow cytometry, ELISA and quantitative PCR, as well as various histological and morphometric assessments of the rodent lungs.

Additionally, Dr. Teodorescu collaborates with several other groups on campus to deepen our knowledge of pathophysiology of OSA, its cardiovascular consequences, and treatments targeting OSA phenotypes.