title: Formaldehyde Induces Rho-Associated Kinase Activity to Evoke Airway Hyperresponsiveness.
abstract: Formaldehyde, a common indoor air pollutant, exacerbates asthma and synergizes with allergen to induce airway hyperresponsiveness (AHR) in animal models. The mechanisms mediating formaldehyde-induced AHR remain poorly understood. We posit that formaldehyde modulates agonist-induced contractile response of human airway smooth muscle (HASM) cells to elicit AHR. HASM cells were exposed to formaldehyde or vehicle and agonist-induced intracellular Ca2+([Ca2+]i) and myosin light-chain phosphatase (MYPT1) phosphorylation were determined. Air-liquid interface-differentiated human bronchial epithelial (HBE) cells were exposed to formaldehyde or vehicle and cocultured with HASM cells. Agonist-induced [Ca2+]iand MYPT1 phosphorylation were determined in the cocultured HASM cells. Precision-cut human lung slices were exposed to PBS or varying concentrations of formaldehyde, and then carbachol-induced airway narrowing was determined 24 hours after exposure. HASM cells were transfected with nontargeting or nuclear factor erythroid-derived 2, like 2 (Nrf-2)-targeting small interfering RNA and exposed to formaldehyde or vehicle, followed by determination of antioxidant response (quinone oxido-reductase 1 and thioredoxin 1) and basal and agonist-induced MYPT1 phosphorylation. Formaldehyde enhanced the basal Rho-kinase activity and MYPT1 phosphorylation with little effect on agonist-induced [Ca2+]iin HASM cells. Formaldehyde induced Nrf-2-dependent antioxidant response in HASM cells, although the MYPT1 phosphorylation was independent of Nrf-2 induction. Although HBE cells exposed to formaldehyde had little effect on agonist-induced [Ca2+]ior MYPT1 phosphorylation in cocultured HASM cells, formaldehyde enhanced carbachol-induced airway responsiveness in precision-cut human lung slices. In conclusion, formaldehyde induces phosphorylation of the regulatory subunit of MYPT1, independent of formaldehyde-induced Nrf-2 activation in HASM cells. The findings suggest that the Rho kinase-dependent Ca2+sensitization pathway plays a role in formaldehyde-induced AHR.
authors.affiliation: 1 Rutgers Institute for Translational Medicine & Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jude
authors.affiliation: 1 Rutgers Institute for Translational Medicine & Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Koziol-White
authors.affiliation: 1 Rutgers Institute for Translational Medicine & Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Scala
authors.affiliation: 1 Rutgers Institute for Translational Medicine & Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: Edwin
authors.initials: E
authors.lastname: Yoo
authors.affiliation: 1 Rutgers Institute for Translational Medicine & Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: William
authors.initials: W
authors.lastname: Jester
authors.affiliation: 2 Monell Chemical Senses Center, Philadelphia, Pennsylvania.
authors.forename: Christopher
authors.initials: C
authors.lastname: Maute
authors.affiliation: 2 Monell Chemical Senses Center, Philadelphia, Pennsylvania.
authors.forename: Pamela
authors.initials: P
authors.lastname: Dalton
authors.affiliation: 1 Rutgers Institute for Translational Medicine & Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: Reynold
authors.initials: R
authors.lastname: Panettieri
keywords: Ca2+ sensitization; airway hyperresponsiveness; airway smooth muscle; asthma; formaldehyde