Biomarkers in Exhaled Breath Condensates in Acute Lung Injury: Early Detection and Outcome Predictors

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the leading causes of mortality and morbidity in the intensive care unit (ICU). The causes of ALI/ARDS differ from patient to patient, including sepsis, aspiration, systemic inflammation, trauma, blood transfusion, etc. With early detection and treatment, the survival rate may be improved significantly. However, it is often difficult to differentiate ALI/ARDS from cardiogenic pulmonary edema or other causes, even with advanced technology and invasive tools. A potential tool is the breath chemical test, ranging from exhaled gas measurement, such as exhaled nitric oxide or carbonic monoxide, to volatile organic compound determination and nonvolatile biomarker profiling. Being completely noninvasive, sampling of the exhaled breath condensates (EBC) allows clinicians and researchers to assess body functions in an easier and flexible manner. Exhaled breath contains thousands of volatile and nonvolatile compounds in trace amounts. Therefore, it is not until recently, after the development of highly sensitive cutting-edge technologies in sample analysis, that the evaluation of this type of human specimens becomes possible. Advanced technologies in proteomics, metabolomics, GC/LC-Mass Spectrometry and pattern recognition computation generate a field of exhaled biomarker profiling, called "breathomics." After the establishment of the metabolomic profiling of EBC in patients with ALI, ARDS or cardiogenic pulmonary edema, a useful and powerful noninvasive tool for ALI/ARDS diagnosis and outcome prediction could be set up.

Metabolomics, or metabonomics, is a large-scale approach to monitoring as many as possible of the compounds involved in cellular processes in a single assay to derive metabolic profiles. Although metabolomics first referred to the monitoring of individual cells and metabonomics referred to multicellular organisms, these terms are now often used interchangeably. Metabolic changes occur through a number of mechanisms, including direct genetic regulation and alterations in enzymatic and metabolic reactions. Metabolomics allows for a global assessment of a cellular state within the context of the immediate environment, taking into account genetic regulation, altered kinetic activity of enzymes, and changes in metabolic reactions. Thus, compared with genomics or proteomics, metabolomics reflects changes in phenotype and therefore function. Techniques applied to metabolic profiling include nuclear magnetic resonance (NMR) and mass spectrometry (MS). Metabolomics have the advantage of being capable of searching for proteins or metabolites in the blood or urine. Metabolomics may be useful for understanding metabolic imbalances and for diagnosis of human disease. Over 30 endogenous metabolites have been studied in breast tissue, and breast cancer show elevated total choline-containing compounds (tCho), low glycerophosphocholine, and low glucose compared with benign tumors or healthy tissue. Similar to breast cancer, prostate cancer exhibits a distinct metabolic profile characterized by high tCho and phosphocholine levels, along with an increase in the glycolytic products lactate and alanine. In prostate cancer, citrate may also be a marker of responsiveness to treatment. These results show the potential utility of metabolomics in cancer diagnosis and clinical evaluation.

Breath chemical tests have a broad spectrum of applications ranging from exhaled nitric oxide fraction (FeNO) measurement to monitor the effect of anti-inflammatory treatment in asthma, to volatile organic compound (VOC) determination and nonvolatile biomarker profiling in the cooled breath sample called exhaled breath condensate (EBC). Being completely noninvasive, sampling of the breath allows clinicians and researchers to assess different body functions in a flexible manner. Therefore, breath testing is considered to be a potentially ideal candidate for screening purposes. Besides widely known constituents such as nitrogen, oxygen, carbon dioxide, inert gases and water vapour, exhaled breath also consists of thousands of volatile and nonvolatile components, mainly in trace amounts, making detection a challenging task. The use of innovative "-omics" technologies, including proteomics, metabolomics, mass spectromics, gas chromatography/mass spectrometry (GC-MS) and ion mobility spectrometries, offers great potential for the field of exhaled biomarker profiling. Unlike bronchoalveolar lavage (BAL) and sputum induction which involves inhalation of hypertonic saline to induce cough and possibly bronchoconstriction, EBC does not influence airway function or cause inflammation. It can be easily and safely performed on patients with severe illness and even allows for repeated measurements to be taken. As such, this is a relatively new field with potential for more studies to be performed to investigate acute lung injury by metabolomics.