Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis.

Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the bleomycin-induced PF mouse model has improved our understanding of exogenous factor-induced fibrosis, the mechanism governing endogenous factor-induced fibrosis remains unknown. Here, we find that Ifngr1-/-Rag2-/- mice, which lack the critical suppression factor for group 2 innate lymphoid cells (ILC2), develop PF spontaneously. The onset phase of fibrosis includes ILC2 subpopulations with a high Il1rl1 (IL-33 receptor) expression, and fibrosis does not develop in ILC-deficient or IL-33-deficient mice. Although ILC2s are normally localized near bronchioles and blood vessels, ILC2s are increased in fibrotic areas along with IL-33 positive fibroblasts during fibrosis. Co-culture analysis shows that activated-ILC2s directly induce collagen production from fibroblasts. Furthermore, increased IL1RL1 and decreased IFNGR1 expressions are confirmed in ILC2s from individuals with idiopathic PF, highlighting the applicability of Ifngr1-/-Rag2-/- mice as a mouse model for fibrosis research.

Elevated international normalized ratio associated with concomitant warfarin and erlotinib.

PURPOSE: The case of a patient who developed elevated International Normalized Ratio (INR) values after concomitant administration of warfarin and erlotinib is reported. SUMMARY: A 47-year-old Caucasian man with a history of atrial fibrillation, anxiety, and a 40-pack-year smoking history was diagnosed with advanced, moderately differentiated adenocarcinoma of the lung. Soon after being diagnosed with non-small-cell lung cancer, warfarin was initiated for the treatment of a venous thromboembolism. The patient's warfarin dosage was adjusted to reach a target INR of 2-3. His INR was relatively stable (2.1-3.2) for at least eight weeks before erlotinib was added to the chemotherapy regimen. The patient developed a well-disseminated rash and diarrhea soon after starting erlotinib. Seven days after the initiation of erlotinib therapy, the patient's INR value increased from 2.8 to 5.3, with no concurrent changes in warfarin dosage, other medications, or diet. After withholding two doses of warfarin, the patient's INR value increased to 9.1, and the patient developed an elbow hematoma. His anticoagulation was rapidly reversed with the administration of subcutaneous phytonadione. The patient elected to discontinue erlotinib nine days after its initiation. The next day, his INR value was 2.4. The patient returned to the hematology-oncology clinic for follow-up two days later, where his INR was found to be 0.9. CONCLUSION: Concomitant administration of erlotinib and warfarin resulted in an increase in INR values in a 47-year-old man with advanced lung cancer.