Respiratory Inflammation & Immunology


 
LRRI’s Immunology Division has experience and expertise in the areas of:
  • Lung infection and inflammation
  • Asthma/chronic obstructive pulmonary disease (COPD)
  • Airway remodeling
  • Physiology of sleep apnea
  • Mucin physiology
  • Lung responses to chemical terrorism
  • Lung responses to pre- and post-natal exposures to environmental pollutants, including cigarette smoke, diesel exhaust, and silica
 

 

 

Key Capabilities:

Lung inflammation: Inflammation is an essential component of many lung diseases, including asthma, COPD, lung cancer, and granulomatous lung diseases. LRRI scientists have observed in rat lung that chronic, silicotic granulomas are initiated late and coincide with the initiation of lung inflammation. Scientists demonstrated that mouse strains susceptible to Cryptococcus neoformans have impaired Th1 responses, and that nicotine treatment inhibits inflammation and exacerbates lung infections caused by influenza virus and Cryptococcus neoformans. Together, these results suggest that while excessive inflammation causes lung injury, adequate inflammation is important to protect lungs from pathogenic infections. LRRI is also evaluating the role of inflammation in a murine model of cigarette smoke-induced emphysema.

Mucins in lung physiology: Airway mucus is an important component in the airway defense against pathogens, where it immobilizes/kills invading pathogens. However, excessive mucus production affects gas exchange and is a key pathophysiological feature in patients with asthma, COPD, and cystic fibrosis. Therefore, homeostasis of mucus formation is important for normal lung function. We have shown the importance of apoptosis in resolution of mucus cell hyperplasia. LRRI observes that in humans a lower risk of developing mucus hypersecretions might be associated with polymorphism in an apoptosis-modulating gene –- p53This finding could be important for developing therapeutic interventions for controlling mucus production in patients with asthma, chronic bronchitis, and COPD.

Neuronal control of breathing: It is becoming increasingly clear that diseases such as severe sleep apnea and sudden infant death syndrome might result from dysregulation of central ventilatory responses.  LRRI scientists have  identified several respiratory centers in the central nervous system that control breathing responses. In addition, pulmonary C-fibers might be affected by cigarette smoke and modulate some parameters of lung inflammation in diseases such as asthma and COPD. Sarin, one of the most toxic nerve agents, causes death through respiratory failure; however, the mechanism that causes respiratory death is not known. Recently, LRRI research showed that death was not due to bronchoconstriction (as previously believed) but due to loss of the mechanism responsible for the control of central breathing. This finding should allow for better therapeutic interventions for sarin toxicity.

Prenatal and post-natal exposure to cigarette smoke: Epidemiologically, children from smoking mothers have a significantly higher risk of developing asthma.  LRRI scientists have developed mouse models to test the effects of prenatal exposure to cigarette smoke and wood smoke, respectively, on the development of airway hyperactivity. Our research suggested that changes in the lung-specific phosphodiesterase play a critical role in the induction of airway hyperresponsiveness that can be corrected by phosphodiesterase-specific inhibitors –- a promising treatment avenue. Additionally, it was observed that second-hand cigarette smoke decreases Th-1 cytokines and exacerbates respiratory syncytial virus infection. This is an important finding with a strong implication for the development of asthma among children.

 

Future Research

 

Lung diseases are the major cause of human morbidity and mortality. The primary cause of lung diseases such as COPD/emphysema and lung cancer is inhalation of cigarette smoke. These diseases have a poor prognosis, and the mechanism(s) by which cigarette smoke promotes these diseases is essentially unknown.

 

Prenatal exposure to cigarette smoke is also a major cause of childhood asthma. Moreover, the incidence of lung diseases has been steadily increasing among human immunodeficiency virus (HIV)-positive patients and is the major cause of death in these patients. Over 70% of HIV patients smoke cigarettes, and diseases such as COPD and lung cancer are seen in these patients at very early ages (i.e., starting as early as late 30s and early 40s). This occurs even when the patients are taking effective antiretroviral drugs and show a “normal” CD4 count. Thus, even latent HIV strongly promotes lung diseases caused by cigarette smoke. This has alarmed the National Institutes of Health (NIH), which is trying to find out how cigarette smoke promotes and exacerbates lung diseases in HIV patients.

 

LRRI’s Immunology Division has developed appropriate animal models to study COPD, asthma, and lung cancer. Because susceptibility to COPD varies among people, it is also likely that LRRI research will identify susceptibility factors for human COPD.

 

Another area of research that is currently in the national interest is countermeasures against chemical terrorism. Potential terrorism chemicals, such as the nerve gas sarin and sulfur mustard, primarily affect the lung. Sarin causes respiratory failure, while sulfur mustard induces chronic lung diseases. Several LRRI scientists in the Immunology Division have developed animal models to study the toxicity of these chemicals.  We hope our research findings will provide a better understanding in the areas of central control of respiration, lung fibrosis, and neuroimmune interaction.