Prakash, Y. S.

Beyond the structural changes, features including the dysregulation of endoplasmic reticulum (ER) stress response and increased senescence characterize the lung aging. ER stress response and senescence have been reported to be induced by factors like cigarette smoke. Therefore, deciphering the mechanisms underlying ER and senescent pathways interaction has become a challenge. In this review we highlight the known and unknown regarding ER stress response and senescence and their cross talk in aged lung.

Maternal infection is a risk for preterm delivery. Preterm newborns often require supplemental oxygen to treat neonatal respiratory distress. Newborn hyperoxia exposure is associated with airway and vascular hyperreactivity, while the complications of maternal infection are variable. In a mouse model of prenatal maternal intraperitoneal lipopolysaccharide (LPS, embryonic day 18) with subsequent newborn hyperoxia (40% oxygen × 7 days) precision-cut living lung slices were used to measure intrapulmonary airway and vascular reactivity at 21 days of age. Hyperoxia increased airway reactivity to methacholine compared to room air controls. Prenatal maternal LPS did not alter airway reactivity in room air. Combined maternal LPS and hyperoxia exposures increased airway reactivity vs. controls, although maximal responses were diminished compared to hyperoxia alone. Vessel reactivity to serotonin did not significantly differ in hyperoxia or room air; however, prenatal maternal LPS appeared to attenuate vessel reactivity in room air. Following room air recovery, LPS with hyperoxia lungs displayed upregulated inflammatory and fibrosis genes compared to room air saline controls (TNFαR1, iNOS, and TGFβ). In this model, mild newborn hyperoxia increases airway but not vessel reactivity. Prenatal maternal LPS did not further increase hyperoxic airway reactivity. However, inflammatory genes remain upregulated weeks after recovery from maternal LPS and newborn hyperoxia exposures.

Supplemental O2 (hyperoxia) is necessary for preterm infant survival but is associated with development of bronchial airway hyperreactivity and childhood asthma. Understanding early mechanisms that link hyperoxia to altered airway structure and function are key to developing advanced therapies. We previously showed that even moderate hyperoxia (50% O2) enhances intracellular calcium ([Ca2+]i) and proliferation of human fetal airway smooth muscle (fASM), thereby facilitating bronchoconstriction and remodeling. Here, we introduce cellular clock biology as a novel mechanism linking early oxygen exposure to airway biology. Peripheral, intracellular clocks are a network of transcription-translation feedback loops that produce circadian oscillations with downstream targets highly relevant to airway function and asthma. Premature infants suffer circadian disruption whereas entrainment strategies improve outcomes, highlighting the need to understand relationships between clocks and developing airways. We hypothesized that hyperoxia impacts clock function in fASM and that the clock can be leveraged to attenuate deleterious effects of O2 on the developing airway. We report that human fASM express core clock machinery ( PER1, PER2, CRY1, ARNTL/BMAL1 , CLOCK) that is responsive to dexamethasone (Dex) and altered by O2. Disruption of the clock via siRNA-mediated PER1 or ARNTL knockdown alters store-operated calcium entry (SOCE) and [Ca2+]i response to histamine in hyperoxia. Effects of O2 on [Ca2+]i are rescued by driving expression of clock proteins, via effects on the Ca2+ channels IP3R and Orai1. These data reveal a functional fASM clock that modulates [Ca2+]i regulation, particularly in hyperoxia. Harnessing clock biology may be a novel therapeutic consideration for neonatal airway diseases following prematurity.