Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung

Abstract

Children are uniquely susceptible to ozone because airway and lung growth continue for an extensive period after birth. Early-life exposure of the rhesus monkey to repeated ozone cycles results in region-specific disrupted airway/lung growth, but the mediators and mechanisms are poorly understood. Substance P (SP), neurokinin-1 receptor (NK-1R); and nuclear receptor Nur77 (NR4A1) are signaling pathway components involved in ozone-induced cell death. We hypothesize that acute ozone (AO) exposure during postnatal airway development disrupts SP/NK-1R/Nur77 pathway expression and that these changes correlate with increased ozone-induced cell death. Our objectives were to 1) spatially define the normal development of the SP/NK-1R/Nur77 pathway in conducting airways; 2) compare how postnatal age modulates responses to AO exposure; and 3) determine how concomitant, episodic ozone exposure modifies age-specific acute responses. Male infant rhesus monkeys were assigned at age 1 mo to two age groups, 2 or 6 mo, and then to one of three exposure subgroups: filtered air (FA), FA+AO (AO: 8 h/day × 2 days), or episodic biweekly ozone exposure cycles (EAO: 8 h/day × 5 days/14-day cycle+AO). O3 = 0.5 ppm. We found that 1) ozone increases SP/NK-1R/Nur77 pathway expression in conducting airways, 2) an ozone exposure cycle (5 days/cycle) delivered early at age 2 mo resulted in an airway that was hypersensitive to AO exposure at the end of 2 mo, and 3) continued episodic exposure (11 cycles) resulted in an airway that was hyposensitive to AO exposure at 6 mo. These observations collectively associate with greater overall inflammation and epithelial cell death, particularly in early postnatal (2 mo), distal airways.

Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity

“…NR4A1 localized to isolectin-positive blood vessels and to perivascular cells that positively stained for the AP marker PDGFRα. These data suggest high constitutive expression of NR4A1 in APs, but also confirm promiscuous expression in multiple cell types (34)(35)(36)(37)(38)(39). We also investigated whether Nr4a1 expression was dynamically regulated in AT in vivo in physiologically relevant contexts.…”

Transcriptional Effects of Ozone and Impact on Airway Inflammation

“…For example, BAL γ-glutamyl transferase activity and lung inflammation were only significantly enhanced after acute ozone in adolescent and young adult rats. The susceptibility of children to the detrimental effects of ozone exposure may be due to the need for airway and lung growth to continue after birth (86). Neurokinin signaling is involved in ozone-induced cell death and in male infant rhesus monkeys ozone increased neurokinin pathway expression in the conducting airways.…”

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

“…Although use of the primate models is steadily declining, largely attributable to cost and ethical issues, macaques have recently been used to evaluate the impact of ozone on postnatal lung maturation in nonhuman primates by Murphy and coworkers (250), who noted that susceptibility to ozone damage is age dependent and that prior ozone exposure modulates the response to subsequent ozone exposure. These data have clearly translatable information to how children living in polluted metropolitan areas during key stages of lung development may respond to ozone exposure in later life.…”