Bilirubin as a signaling molecule

For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.     

End-tidal estimates of arterial PCO2 for cardiac output measurement by CO2 rebreathing: A study in patients with cystic fibrosis and healthy controls

We set out to determine the effects of various estimates of arterial PCO₂ (PaCO₂) on calculation of cardiac output (Q) by the indirect Fick (CO₂) method in healthy children and children with cystic fibrosis (CF), and to develop a prediction equation for children for PaCO₂, based on end-tidal PCO₂ (PetCO₂). The study had 3 parts: 1) Twenty-three healthy children exercised lightly and moderately while arterialized capillary blood gases and PetCO₂ were measured simultaneously so that a prediction equation for PaCO₂ could be derived from PetCO₂. Cardiac output was measured by CO₂ rebreathing at each workload; different values for PaCO₂ (measured in arterialized capillary blood, end-tidal, and PaCO₂ derived from the Bohr equation assuming normal dead space) were used to calculate Q; 2) our equation PaCO₂ = 0.647 PetCO₂ + 12.4 was tested prospectively to measure Q in 9 healthy children; and 3) cardiac output based on arterialized capillary PaCO₂ was compared with that based on Jones-corrected PetCO₂ during light and moderate exercise in 16 CF patients whose forced expiratory volume in 1 second (FEV₁) range from normal to 37% predicted. Our results have shown that in health children end tidal based-estimates of PaCO₂ tended to overestimate Q, whereas PaCO₂ values derived by the Bohr equation and assuming normal dead space tended to underestimate Q, compared with Q calculated from directly measured PaCO₂. Our prediction equation resulted in good agreement compared with directly measured PaCO₂ when used to calculate Q (mean difference, +1.3%; range, +9% to −13%). CF patients with little or no airway obstruction had results similar to healthy controls, but those with severe airway obstruction had lower values for Q when PetCO₂ was used instead of directly measured PaCO₂. We conclude that estimates of PaCO₂ from PetCO₂ are not reliable in patients with moderately severe pulmonary disease due to CF. In healthy children, the prediction equation for PaCO₂ from PetCO₂ derived in the present study gives results superior to other bloodless methods currently in use for computation of Q by the indirect Fick (CO₂) method. Pediatr Pulmonol. 1996; 22:154–160. © 1996 Wiley-Liss, Inc.     

Analysis of naturally processed peptides eluted from HLA DRB1 *0402 and *0404

Understanding the structural features of naturally processed peptides found within the major histocompatibility complex (MHC) class II peptide binding groove from disease-associated MHC molecules may provide insights into the nature of potential disease-related antigens. Class II MHC/peptide complexes were purified by immunoaffinity from transformed B cell lines homozygous for DRB1*0404 (an allele associated with rheumatoid arthritis) and *0402 (a closely related allele not associated with this disease). Peptides were eluted at acidic pH, fractionated by reversed phase HPLC, and analyzed by capillary electrophoresis. Those fractions containing a single dominant peptide were sequenced by automated Edman degradation and tandem mass spectrometry. The predominant peptide species identified came from non-polymorphic regions of the HLA class I molecules expressed by each cell line. Peptides from DRB1*0404 were found to be nested clusters derived from positions 26–43 of the HLA-B and -C α-chain. DRB1*0402 contained as the predominant peptide species a nested cluster from positions 129–145 of the HLA-B α-chain. The primary structure of the class I derived peptides was consistent with that seen by peptides exhibiting promiscuous DR binding behavior. Processing of MHC-derived peptides by MHC class II molecules is a common occurrence in the transformed B cell lines analyzed. © 1996 Wiley-Liss, Inc.