Acute exogenous lipoid pneumonia is a rare non-infectious pulmonary disease caused by inhalation of oil. It was first described in 1925 by Laughlin[8]. Lipid pneumonia can be divided into two types: endogenous and exogenous lipoid pneumonia[7]. Exogenous lipoid pneumonia may result from the aspiration of food and lipids, and is commonly associated with the use of mineral oils and liquid paraffin as laxatives[9-11]. Although most cases are asymptomatic, common symptoms include cough, dyspnea, chest pain, pleural effusion, fever and hemoptysis[9]. The prevalence of AELP is less than one in 10 million[9]. However, in the study of high-risk groups, the incidence rate of lipid pneumonia in patients with chronic diseases rose to 14.6%[12]. In recent years, proteomics has been widely used in the pathogenesis of various diseases and the screening of therapeutic drugs. However, there is no relevant research on proteomics and AELP. Therefore, the biological processes, signal pathways and key genes involved in AELP are explored through proteomics technology to deepen the understanding of the pathogenesis of AELP and provide theoretical basis for the prevention of AELP and the development of specific therapeutic drugs.
In this study, proteomics was used to timely detect the protein expression profile of the lung tissues of mice with AELP. The results showed that there were 1253 DEPs, including 843 up-regulated proteins and 410 down-regulated proteins. The GO enrichment analysis of DEGs shows that DEPs are mainly enriched in the processes of integrin binding, proteoglycan binding, chemokine receiver binding, receiver regulator binding, and cytotoxic activity.
The proteins with high connectivity were PADI4, IGF2, SMPDL3B, UHRF1, ANXA8, DEFB4, F3, MK167, SLC39A4, LIMD1 and GJA1. All the above proteins were validated, and results indicated that PADI4, IGF2, SMPDL3B, UHRF1, ANXA8, MK167, SLC39A4, LIMD1 and GJA1 were significantly upregulated in experimental group compared to the control group. SMPDL3B, ANXA8, MK167, SLC39A4, LIMD1 are mainly related to the occurrence, development and treatment of renal podocyte injury, lung cancer, melanoma, gallbladder cancer, etc[13-17]. However, the function of the PADI4, IGF2, UHRF1, DEFB4 and GJA1 in AELP is unknown and further investigation is needed.
PADI4 is an enzyme that catalyzes the conversion of arginine in protein peptide chain to citrulline[18]. They are found in a wide range of cells and tissues, among which PADI4 is found in macrophages, monocytes, granulocytes and cancer cells[18]. Some studies have found that PADI4 is closely related to the pathogenesis of various tumors and rheumatoid arthritis (RA)[18, 19]. Cheng et al found that hypoxia related PADI4 is related to the classical activation (M1) of macrophages, reducing the expression of PADI4 and improving the hypoxia environment, inflammatory reaction can be alleviated, especially in RA[19]. IGF2, a member of the insulin family, plays an important role in in fibrosis of lung, heart, liver and kidney[19, 20]. In the study conducted by Bayati et al, induced pluripotent stem cells can inhibit experimental bleomycin-induced pulmonary fibrosis by regulating insulin-like growth factor signal[21]. In addition, IGF-2 and its receptors can activate the known TGF-β pro-fibrotic pathway and disrupt the balance of matrix proteases and their inhibitors, leading to excessive ECM deposition and inducing the differentiation of fibroblasts into myofibroblasts, thus promoting the occurrence and development of fibrosis[20]. UHRF1 is a basic epigenetic regulator with multiple functions and has been recognized in many diseases[22]. Previous studies have shown that UHRF1 is involved in many processes, including histone modification and DNA methylation[23, 24]. A recent study showed that TGF-β1–mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts[25]. GJA1, also known as Cx43, is one of these connexins. It is prominently featured in the immunological synapse, thus making it the prime target for investigations in immune cells, such as macrophages[26]. In macrophages, Cx43-dependant intercellular signal transfer is involved in a plethora of physiological and pathophysiological processes, such as migration, phagocytosis and antigen-Presentation[27]. Increases in Cx43 expression consequently enhances the migratory ability of macrophages[27]. Additionally, Cx43 knockout macrophages enhanced the alveolar recruitment of neutrophils[28]. However, the number of neutrophils migrating in the lung of infected Cx43 mouse model was monitored by intratracheal instillation of Pseudomonas aeruginosa lipopolysaccharide (LPS), Sarieddine et al found that the recruitment of neutrophils caused by LPS increased in the mutant Cx43 mouse model expressing enhanced channel conductivity (P<0.05)[29]. The results showed that Cx43 might be a specific target for recruitment of neutrophils into the airway, the conclusion is controversial. An animal study of acute lung injury caused by seawater inhalation showed that seawater inhalation enhanced the phosphorylation of Cx43 on Ser368 and reached a peak at 4 h. It shows that seawater inhalation induced the expression of p-Cx43 through PKC pathway, and participated in the occurrence and development of lung inflammation and pulmonary edema [30]. As such,PADI4, IGF2, UHRF1, DEFB4 and GJA1 may be potential biomarker of AELP.