ABSTRACT
Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.
Subject(s)
Drug Design , Immunomodulation/drug effects , Lymphocytes/drug effects , Lymphocytes/metabolism , Receptors, Aryl Hydrocarbon/agonists , Wound Healing/drug effects , Wound Healing/immunology , Animals , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/pharmacology , Colitis/etiology , Colitis/metabolism , Colitis/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Drug Stability , Gene Expression , Humans , Interleukins/biosynthesis , Intestinal Mucosa/drug effects , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Ligands , Lymphocytes/immunology , Mice , Models, Molecular , Molecular Conformation , Receptors, Aryl Hydrocarbon/chemistry , Regeneration , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Wound Healing/genetics , Interleukin-22ABSTRACT
BACKGROUND: Readmissions after cardiac surgery are common and associated with increased morbidity, mortality and cost of care. Policymakers have targeted coronary artery bypass grafting to achieve value-oriented health care milestones. We explored the causes of readmission following cardiac surgery among a regional consortium of hospitals. METHODS: Using administrative data, we identified patients readmitted to the same institution within 30 days of cardiac surgery. We performed standardized review of readmitted patients' medical records to identify primary and secondary causes of readmission. We evaluated causes of readmission by procedure and tested for univariate associations between characteristics of readmitted patients and nonreadmitted patients in our clinical registry. RESULTS: Of 2218 cardiac surgery patients, 272 were readmitted to the index hospital within 30 days for a readmission rate of 12.3%. Median time to readmission was 9 days (interquartile range 4-16 days) and only 13% of patients were evaluated in-office before readmission. Readmitted patients were more likely to have had valve surgery (31.3% vs 22.7%) than patients not readmitted. Readmitted patients were also more likely to have preoperative creatinine more than or equal to 2 mg/dL (P = .015) or congestive heart failure (CHF) (P = .034), require multiple blood transfusions or sustained inotropic support (P < .001), and experience postoperative atrial fibrillation (P = .022) or renal insufficiency (P < .001). Infection (26%), pleural or pericardial effusion (19%), arrhythmia (16%), and CHF (11%) were the most common primary etiologies leading to readmission. CONCLUSIONS: Ensuring early follow-up for high-risk patient groups while improving early detection and management of the principal drivers of readmission represent promising targets for decreasing readmission rates.