Wallerich, Samantha

Airway inflammation is a key feature of asthma, with inflammatory cytokines (e.g., TNFα and IL‐13) triggering hyperreactivity (enhance contractile state) and proliferation and remodeling (enhanced synthetic state) in airway smooth muscle (ASM). We hypothesize that TNFα and IL‐13 induce sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) stress, thereby altering expression of mitochondrial fission/fusion proteins (dynamin‐related protein ‐ Drp1 and mitofusin ‐ Mfn2) with downstream impact on ASM Ca 2+ regulation and contractility as well as proliferation. Human ASM cells were isolated from lung specimens obtained incidental to patient surgery. We found that after 24 h exposing ASM cells to TNFα and IL‐13: 1) expression of SR/ER stress protein markers (PERK, calnexin and XBP1) increased; 2) Drp1 expression increased Mfn2 expression decreased; 3) mitochondrial fragmentation increased; 4) [Ca 2+ ] cyt and [Ca 2+ ] mito responses to ACh stimulation were uncoupled; 5) net [Ca 2+ ] cyt increased; 6) contractility increased; and 7) cell proliferation increased. Together these results suggest that inflammation induces SR/ER stress that leads to changes in Mfn2 and Drp1 expression, which alter mitochondrial dynamics and Ca 2+ regulation resulting in ASM hyperreactivity and remodeling. Grant Funding Source : Supported by NIH grant HL74309 (GCS)