Progressive Lung Injury, Inflammation, and Fibrosis in Rats Following Inhalation of Sulfur Mustard

Abstract

Sulfur mustard (SM) inhalation causes debilitating pulmonary injury in humans which progresses to fibrosis. Herein, we developed a rat model of SM toxicity which parallels pathological changes in the respiratory tract observed in humans. SM vapor inhalation caused dose (0.2 - 0.6 mg/kg) related damage to the respiratory tract within 3 d of exposure. At 0.4 - 0.6 mg/kg, ulceration of the proximal bronchioles, edema and inflammation were observed, along with a proteinaceous exudate containing inflammatory cells in alveolar regions. Time course studies revealed that the pathologic response was biphasic. Thus, changes observed at 3 d post-SM were reduced at 7 d - 16 d; this was followed by more robust aberrations at 28 d, including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis. Histopathologic changes were correlated with biphasic increases in BAL cell and protein content and PCNA expression. Proinflammatory proteins RAGE, HMGB1, and MMP-9 also increased in a biphasic manner following SM inhalation, along with SP-D. TNFα and iNOS, inflammatory proteins implicated in mustard lung toxicity, and the proinflammatory/profibrotic protein, Gal-3, were upregulated in alveolar macrophages and in bronchiolar regions at 3 d and 28 d post-SM. Inflammatory changes in the lung were associated with oxidative stress, as reflected by increased expression of HO-1. These data demonstrate a similar pathologic response to inhaled SM in rats and humans suggesting that this rodent model can be used for mechanistic studies and for the identification of efficacious therapeutics for mitigating toxicity.

Clinical applications of mesenchymal stromal cell-based therapies for pulmonary diseases: An Update and Concise Review

“…Sulfur mustard (SM) is a potent alkylating toxic chemical compound that targets several organs, especially the lungs. Acute lung injury due to SM inhalation causes the formation of airway fibrin casts that obstruct airways at multiple levels, which is associated with chronic obstructive pulmonary deficiency, leading to acute respiratory failure and death 111 . Currently, effective medical countermeasures for SM are lacking.…”

LncRNA MEG3amelioratesNiOnanoparticles‐induced pulmonary inflammatory damage via suppressing the p38 mitogen activated protein kinases pathway

“…As is known to us, even slight inflammation could cause coughing, phlegm and loss of appetite 37 . Severe cases may lead to breathlessness, pulmonary fibrosis and cancer 38 .…”

“…As is known to us, even slight inflammation could cause coughing, phlegm and loss of appetite. 37 Severe cases may lead to breathlessness, pulmonary fibrosis and cancer. 38 Especially, the particles in the environment are more likely to cause pulmonary damage and further lead to pneumoconiosis as well as silicosis.…”

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin

“…66 Both mouse and rat models of SM injury by intratracheal inhalation and NM by intratracheal aerosolization have been developed. 71,72 These animals are exposed to a range of mustard doses and followed from 1 to 28 days post-exposure, with an assessment of lung tissue and lining, bronchoalveolar lavage (BAL) fluid, and immune cells, as well as pulmonary function analyses and live animal MRI/ CT scanning. 73 Histopathological effects of SM on the lung include early thickening of the epithelium and airways that become more prominent over time.…”

“…These inflammatory macrophages are present within 1 day post-exposure, and their size and numbers increase over time. 71 Further mechanistic studies focused on the contribution of distinct subsets of macrophages and the mediators they release on acute lung injury and chronic lung fibrosis induced by SM. These subsets develop from bone marrow precursor cells and are designated as M1 and M2 which develop in response to signals in the tissue microenvironment.…”