Research

Area of general research interest:

  • Pulmonary hypertension
  • Asthma
  • Beryllium-induced lung disease
  • Biologic markers of lung disease
  • Exhaled breath analysis
  • Role of nitric oxide (NO) in lung physiology and lung diseases
  • EVI-1 gene in myelodysplastic syndrome

Current programs:

  • Exhaled breath analysis
  • Nitric oxide and carbon monoxide in pulmonary hypertension and asthma
  • Pathobiology of pulmonary hypertension

Investigators:

  • Raed Dweik, (supervisor )
  • Metin Aytekin
  • David Grove
  • Gustavo Heresi,
  • Adriano Tonelli
  • Sarah Haserodt
  • Joseph Cody
  • Alquam Mashir
  • Jennie Newman
  • Frank Cikach
  • Kelly Paschke

Lab photos:

 

Collaborators:

  • Serpil Erzurum, M.D.: Pathobiology, CCF
  • Suzy A. A. Comhair, Ph.D.: Pathobiology, CCF
  • Carol de la Motte, Ph.D.: Pathobiology, CCF
  • Vincent Hascall, Ph.D.: Biomedical Engineering, CCF

Program Highlights:

 

Newsletters:

Click to see Newsletter Summer 2008

Click to see Newsletter Spring 2009

Brief Description:

Exhaled breath analysis: With each breath we exhale, thousands of molecules are expelled in our breath and each one of us has a “smellprint” that can tell a lot about his or her state of health. One can argue that the field of breath analysis is a sold as the field of medicine itself. Hippocrates described fetor oris and fetor hepaticus in his treatise on breath aroma and disease. The end of the 20th century and the beginning of the 21st century, however, have arguably witnessed a revolution in our understanding of the constituents of exhaled breath and the development of the field of breath analysis and testing. A major breakthrough in the scientific study of breath started in the 1970s when Linus Pauling (using gas-liquid partition chromatography analysis) demonstrated the presence of 250 substances in exhaled breath. With modern mass spectrometry (MS) and gas chromatography mass spectrometry (GC-MS) instruments, we can now identify more than 5000 unique substances in exhaled breath. These substances include elemental gases like nitric oxide and carbon monoxide and a multitude of volatile organic compounds. Exhaled breath also carries aerosolized droplets that have other compounds dissolved in them as well. We now have the technology to test for all of these components. Thanks to major breakthroughs in new technologies (infrared, electrochemical, chemiluminescence, and others) and the availability of desktop mass spectrometers, the field of breath analysis has made considerable advances in the 21st century. Several methods are now in clinical use or about ready to enter that arena. Our laboratory has contributed significantly to this field. Dr. Dweik is also a founding member of the International Association for Breath Research (IABR) and an Associate Editor of the Journal of Breath Research (JBR).

Nitric oxide (NO): The discovery that endothelial derived relaxing factor (EDRF) was nitric oxide (NO) brought this highly reactive free radical gas out of relative obscurity as an environmental pollutant and put it on the scientific center stage. This led to an explosion in our knowledge about NO and its role in human physiology and disease. NO is endogenously synthesized by nitric oxide synthases (NOSs) which convert L-arginine to L-citrulline and NO in the presence of oxygen and several cofactors. Three NOSs (type I, II and III) have been identified and are widely expressed in various tissues including the lungs. Once produced, NO is freely diffusible and enters target cells activating soluble guanylate cyclase to produce guanosine 3’, 5’-cyclic monophosphate (cGMP) which mediates the majority of NO effects. NO also diffuses into the airway and can be detected in exhaled breath of all humans. NO is formed in high concentrations in the upper respiratory tract (nasopharynx and paranasal sinuses). Our studies have also conclusively demonstrated that the lower respiratory tract is a significant source of NO in exhaled breath. We have also demonstrated that endogenous NO levels in the lung change rapidly in direct proportion to inspired oxygen which strongly supports a critical role for NO as mediator of ventilation-perfusion coupling in the lung.

Pulmonary hypertension: Pulmonary hypertension (PH), a group of diseases characterized by high pulmonary artery pressures and pulmonary vascular resistance can be either idiopathic (primary) or secondary to an identifiable underlying pulmonary, cardiac, or systemic disease. Idiopathic pulmonary arterial hypertension (IPAH) previously referred to as primary pulmonary hypertension (PPH) is a progressive disease that affects predominantly young and productive individuals, is more common in females, and has a mean survival between 2 to 3 years from the time of diagnosis. Dr. Dweik was a part of the team that initially described low levels of NO in the exhaled breath of patients with PPH. Although this is a far more complex issue than the simple lack of a vasodilator, replacement of NO seems to work well in treating the problem. Our laboratory continues to explore the role of NO in the pathobiology of PH.

Asthma: Patients with asthma have high levels of exhaled NO in their exhaled breath and high levels of NOS II enzyme expression in the epithelial cells of their airways. Although these findings suggest a role for NO in asthma pathogenesis, the exact role of NO in asthma and airway reactivity remains elusive despite intense research in this area. Whether NO is beneficial through its bronchodilator and antioxidant effects or harmful by inducing inflammation remains unclear. Our laboratory made several major contributions to the understanding of the role of NO in the pathobiology, diagnosis and monitoring of asthma.

Chronic Beryllium Disease (CBD, berylliosis): CBD is an occupationally acquired granulomatous lung disease similar to sarcoidosis. It is caused by exposure to Beryllium in genetically susceptible individuals. CBD should be suspected in individuals with beryllium exposure who present with pulmonary symptoms, or have a positive screening blood lymphocyte proliferation test (BeLPT). The diagnosis is confirmed by finding granulomas on TBBX in the appropriate clinical and epidemiological setting. In our laboratory, we found that individuals with CBD have high levels of the inflammatory marker nitric oxide in their exhaled breath providing a potential method for monitoring these patients. Our collaborative work with several laboratories helped clarify the genetic basis of CBD as well as the role of NO in the regulation of the cytokine response to beryllium.

The overall goal of our current studies is to understand lung physiology and pathology through the study of systemic and exhaled biomarkers2008 DweikLab Overview Ven. While our current focus is on the pathobiology of pulmonary hypertension, our work also covers lung physiology as well as the full spectrum of lung diseases that involve the airway (asthma), parenchyma (berylliosis-CBD), and the pulmonary circulation (pulmonary hypertension).