P97 deficiency interferes with the recovery from acute nitrogen mustard-induced respiratory tract injury

Nitrogen mustard (NM) is a vesicant, and the respiratory tract is one of its primary target organs. The recovery following NM exposure is protracted. Despite the existence of numerous theories regarding the toxic effects of NM, but to date, no studies have investigated the global cellular response profiles across distinct phases after NM exposure. Herein, we examined alterations in pulmonary function in mice before and after NM exposure, characterized the biological changes in human bronchial epithelial cells (HBEs) during acute NM exposure and the subsequent post-exposure recovery phase, and further analyzed the impact of p97 deficiency on cell injury. Following acute NM exposure, the expiratory time and total respiratory cycle time were prolonged in mice, whereas the expiratory flow at 50% of tidal volume (EF50) and alveolar volume were reduced. NM rapidly perturbs nucleic acid-associated biological processes within the nucleus, including the cell cycle, chromatin dynamics, mitosis, and RNA processing and splicing, with concomitant upregulation of the expression of relevant proteins. Acute NM exposure for 1 h exerted no effect on total p97 expression level, but promoted the accumulation of p97 in the cytoplasm. In contrast, nuclear p97 expression was increased at 24 h after NM removal. Although p97 deficiency exerted minimal effects on cellular stress responses during the acute exposure phase, it disrupted intracellular material transport, elicited a tendency toward the suppression of nuclear protein expression, and impeded the recovery process after the termination of NM exposure. P97 deficiency primarily repressed the expression of nucleoporins and histones, and inhibited aerobic respiration during the cellular recovery phase. Collectively, these findings suggest that the perturbation of nucleic acid-associated biological processes constitutes the initial and critical event underlying the respiratory toxicity of NM. Furthermore, p97 deficiency impairs material transport, small-molecule metabolism, and mitochondrial function, and prolongs the recovery time in the aftermath of NM exposure.