Formaldehyde Induces Rho-associated Kinase Activity to Evoke Airway Hyperresponsiveness.

Formaldehyde Induces Rho-associated Kinase Activity to Evoke Airway Hyperresponsiveness.

Am J Respir Cell Mol Biol. 2016 May 5;

Authors: Jude J, Koziol-White C, Scala J, Yoo E, Jester W, Maute C, Dalton P, Panettieri R

Abstract
BACKGROUND: 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.
METHODS: HASM cells were exposed to formaldehyde or vehicle and agonist-induced intracellular Ca(2+) ([Ca2+]i), and myosin light chain phosphatase (MYPT1) phosphorylation were determined. Air-liquid interface (ALI)-differentiated human bronchial epithelial (HBE) cells were exposed to formaldehyde or vehicle and co-cultured with HASM cells. Agonist-induced [Ca(2+)]i and MYPT1 phosphorylation were determined in the co-cultured HASM cells. Precision-cut human lung slices (PCLS) were exposed to PBS or varying concentrations of formaldehyde and then carbachol (cch) -induced airway narrowing was determined 24 h post-exposure. HASM cells were transfected with non-targeting (NT) or Nrf-2-targeting (Nrf-2) siRNA, exposed to formaldehyde or vehicle, followed by determination of anti-oxidant response (NQO1 and Trx1) and basal and agonist-induced MYPT1 phosphorylation.
RESULTS: Formaldehyde enhanced the basal Rho-kinase activity and MYPT1 phosphorylation with little effect on agonist-induced [Ca(2+)]i in HASM cells. Formaldehyde induced Nrf-2-dependent anti-oxidant 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 [Ca(2+)]i or MYPT1 phosphorylation in co-cultured HASM cells, formaldehyde enhanced cch-induced airway responsiveness in PCLS.
CONCLUSIONS: Formaldehyde induces phosphorylation of the regulatory subunit of myosin light chain phosphatase (MYPT1), independent of formaldehyde-induced Nrf-2 activation in HASM cells. The findings suggest that Rho kinase-dependent Ca(2+) sensitization pathway plays a role in in formaldehyde-induced AHR.

PMID: 27149505 [PubMed - as supplied by publisher]

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