Differential modulation of lung aquaporins among other pathophysiological markers in acute (Cl2 gas) and chronic (carbon nanoparticles, cigarette smoke) respiratory toxicity mouse models

Abstract

Inhaled toxic chemicals and particulates are known to disrupt lung homeostasis causing pulmonary toxicity and tissue injury. However, biomarkers of such exposures and their underlying mechanisms are poorly understood, especially for emerging toxicants such as engineered nanoparticles and chemical threat agents such as chlorine gas (Cl2). Aquaporins (AQPs), commonly referred to as water channels, are known to play roles in lung homeostasis and pathophysiology. However, little is known on their regulation in toxicant-induced lung injuries. Here, we compared four lung toxicity models namely, acute chemical exposure (Cl2)-, chronic particulate exposure (carbon nanotubes/CNT)-, chronic chemical exposure (cigarette smoke extract/CSE)-, and a chronic co-exposure (CNT + CSE)- model, for modulation of lung aquaporins (AQPs 1, 3, 4, and 5) in relation to other pathophysiological endpoints. These included markers of compromised state of lung mucosal lining [mucin 5b (MUC5B) and surfactant protein A (SP-A)] and lung-blood barrier [protein content in bronchoalveolar lavage (BAL) fluid and, cell tight junction proteins occludin and zona-occludens]. The results showed toxicity model-specific regulation of AQPs measured in terms of mRNA abundance. A differential upregulation was observed for AQP1 in acute Cl2 exposure model (14.71-fold; p = 0.002) and AQP3 in chronic CNT exposure model (3.83-fold; p = 0.044). In contrast, AQP4 was downregulated in chronic CSE model whereas AQP5 showed no significant change in any of the models. SP-A and MUC5B expression showed a decreasing pattern across all toxicity models except the acute Cl2 toxicity model, which showed a highly significant upregulation of MUC5B (25.95-fold; p = 0.003). This was consistent with other significant pathophysiological changes observed in this acute model, particularly a compromised lung epithelial-endothelial barrier indicated by significantly increased protein infiltration and expression of tight junction proteins, and more severe histopathological (structural and immunological) changes. To our knowledge, this is the first report on lung AQPs as molecular targets of the study toxicants. The differentially regulated AQPs, AQP1 in acute Cl2 exposure versus AQP3 in chronic CNT nanoparticle exposure, in conjunction with the corresponding differentially impacted pathophysiological endpoints (particularly MUC5B) could potentially serve as predictive markers of toxicant type-specific pulmonary injury and as candidates for future investigation for clinical intervention.

Secretion of related factors and AMPK/PGC-1 α signal pathway by alveolar macrophages in viral acute lung injury

“…the increase of its level can lead to excessive secretion of mucin, which provides a good medium for virus reproduction, thus aggravating airway inflammation in patients with VALI ( 16); AQP5 is an important water transport channel in the airway and lung tissue. The decrease in its level can lead to too little mucus secretion, which increases the concentration of mucin and provides a good medium for virus reproduction (17). The results showed that the expression levels of MUC5AC and TLR4 in the VALIG were raised than those in the BCG, while the expression level of AQP5 in the VALIG was reduced to that in the BCG.…”

Molecular Impact of Conventional and Electronic Cigarettes on Pulmonary Surfactant

“…Numerous cellular mechanisms governing surfactant homeos impaired following exposure to CS and are reviewed in this sectio [131] BAL = bronchoalveolar lavage; CS = cigarette smoke; CSE = cigarette smoking extract.…”

“…As observed in humans, SP-A varied more heterogeneously after CS exposure, decreasing in three studies, increasing in three others and remaining unchanged in one. Only two studies [114,131] analyzed all four surfactant proteins. One [114] showed that CS caused an increase in the levels of SP-A and SP-D, whereas those of SP-B and SP-C were unchanged; the other [131] showed a CS-induced reduction for every SP.…”

“…Only two studies [114,131] analyzed all four surfactant proteins. One [114] showed that CS caused an increase in the levels of SP-A and SP-D, whereas those of SP-B and SP-C were unchanged; the other [131] showed a CS-induced reduction for every SP.…”

Oro-Respiratory Dysbiosis and Its Modulatory Effect on Lung Mucosal Toxicity during Exposure or Co-Exposure to Carbon Nanotubes and Cigarette Smoke

“…Lung homeostasis is maintained by critical mucosal proteins [26]. For example, surfactant proteins such as SP-A are required for the lubrication of the alveolar lining for normal lung function and the opsonization of microbes.…”