OR2AT4 and OR1A2 counterregulate molecular pathophysiological processes of steroid-resistant inflammatory lung diseases in human alveolar macrophages.

BACKGROUND: Therapeutic options for steroid-resistant non-type 2 inflammation in obstructive lung diseases are lacking. Alveolar macrophages are central in the progression of these diseases by releasing proinflammatory cytokines, making them promising targets for new therapeutic approaches. Extra nasal expressed olfactory receptors (ORs) mediate various cellular processes, but clinical data are lacking. This work investigates whether ORs in human primary alveolar macrophages could impact pathophysiological processes and could be considered as therapeutic targets. METHODS: Human primary alveolar macrophages were isolated from bronchoalveolar lavages of 50 patients with pulmonary diseases. The expression of ORs was validated using RT-PCR, immunocytochemical staining, and Western blot. Changes in intracellular calcium levels were analyzed in real-time by calcium imaging. A luminescent assay was used to measure the cAMP concentration after OR stimulation. Cytokine secretion was measured in cell supernatants 24 h after stimulation by ELISA. Phagocytic ability was measured by the uptake of fluorescent-labeled beads by flow cytometry. RESULTS: We demonstrated the expression of functional OR2AT4 and OR1A2 on mRNA and protein levels. Both ORs were primarily located in the plasma membrane. Stimulation with Sandalore, the ligand of OR2AT4, and Citronellal, the ligand of OR1A2, triggered a transient increase of intracellular calcium and cAMP. In the case of Sandalore, this calcium increase was based on a cAMP-dependent signaling pathway. Stimulation of alveolar macrophages with Sandalore and Citronellal reduced phagocytic capacity and release of proinflammatory cytokines. CONCLUSION: These are the first indications for utilizing olfactory receptors as therapeutic target molecules in treating steroid-resistant lung diseases with non-type 2 inflammation.

Preoperative and intraoperative factors associated with long-term survival in octogenarian cardiac surgery patients.

BACKGROUND: The proportion of octogenarians undergoing cardiac surgery is increasing though few studies have examined the simultaneous impact of preoperative and intraoperative factors on long-term survival in this age group. This study aimed to describe the preoperative clinical and demographic characteristics associated with long-term mortality risk and determine whether intraoperative factors related to surgical and cardiopulmonary bypass techniques impacted upon these. METHODS: Octogenarians undergoing coronary artery bypass grafting (CABG) +/- concomitant valvular procedure between 1992 and 2005 from three institutions were included in this study. The survival data of 606 octogenarians (414 isolated CABG, 192 concomitant valve procedures) were analyzed with multivariable proportional hazard models. RESULTS: There were 271 deaths and 2,675 person years of survival for analysis, and median follow-up was 7.15 years (95% confidence interval 6.47 to 7.82 years). Five-year survival for isolated CABG and concomitant valve procedures was 66.5% and 61.5%, respectively. An increase in mortality risk was attributable to older age, hypercholesterolemia, severely impaired left ventricular function, tobacco smoking history and high creatinine (> or = 0.15 mmol/L). Time spent on cardiopulmonary bypass was the only intraoperative risk factor associated with an increase in mortality risk (hazard ratio 1.01, 95% confidence interval: 1.00 to 1.02; p < 0.001). CONCLUSIONS: This study showed that from the intraoperative parameters examined only time spent on cardiopulmonary bypass was associated with long-term survival. Surgeons may be assisted in patient selection by identifying the factors that influence long-term survival among octogenarians and development of a preoperative risk model specific for this age group.