Remarkable contribution of particulate matter-induced macrophage ferroptosis to the pathology of pulmonary fibrosis

Guangzhe Zheng1,4#, Shihao Bi2#, Jiayu Ren1, Sijin Liu1,3, Bin Shi2*

1Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China

2Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China

3State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China

4Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China

#These authors contributed equally.

Occupational exposure to particulate matter (PM) induced pulmonary fibrosis has aroused broad public concern. Pulmonary interstitial fibrosis is a central pathologic process of pneumoconiosis. Meanwhile, ferroptosis is a newly defined iron-dependent programmed cell death (PCD) that features increased intracellular labile iron and lethal accumulation of lipid peroxidation. Ferroptosis has been found to involve particulate-induced cytotoxicity. Recent studies have suggested that ferroptosis is closely associated with the occurrence and progression of pulmonary fibrosis. Here, we present a mini review to summarize the main mechanisms responsible for PM-induced pulmonary fibrosis via inducing macrophage ferroptosis to provide new insights into basic and clinical research of pulmonary fibrosis.


Particulate matter (PM) is a type of environmental air pollutants. Once inhaled into the human airway, it will trigger a series of disorders of the respiratory system, including pulmonary fibrosis through inflammation1-3. After crossing the air–blood barrier, PMs can even elicit harmful effects on distant organs through blood circulation, including joint injury and nervous system impairment4-6. Recently, it has been recognized that macrophage damage caused by inhalation exposure of PMs is closely associated with fibrogenesis via multiple fibrogenic cytokines, such as transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), interleukin (IL) 1β, IL-4, IL-6, IL-10 and IL-133,7-11. Remarkably, inhalation exposure to PMs could induce alveolar macrophage damage as well as different programmed cell death such as apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis11-14. Especially, ferroptosis is a type of programmed cell death (PCD) characterized by overloading intracellular labile iron and accumulation of lipid peroxide caused by ferrous ion-mediated Fenton reaction15,16, which differs from other PCDs in the sense of biochemical characteristics17. Some studies have revealed that PM-induced macrophage ferroptosis is associated with various pulmonary diseases, including pulmonary fibrosis7,9,14,18. This mini review will focus on how PM-induced macrophage ferroptosis further triggers pulmonary interstitial fibrosis and provide a new perspective for the study of pathogenesis and clinical treatment of fibrosis.

PMs and pulmonary fibrosis

Pneumoconiosis is one of a family of interstitial lung diseases caused by the inhalation and deposition of PMs, including silica particles, asbestos fibers, coal dust and other mineral dust, characterized by chronic pulmonary inflammation and progressive pulmonary fibrosis19. Pneumoconiosis patients suffer from a significantly increased risk of pulmonary functions20,21. Recent epidemiologic studies in humans have indicated that pulmonary fibrosis is closely correlated with PMs21,22.

Experimental data in animals have indicated that pulmonary fibrosis is closely associated with PM exposure23,24. Previous studies have revealed that diffuse interstitial pulmonary fibrosis causes compromised pulmonary compliance and capillary bed, leading to severe respiratory dysfunction25,26.

Silicosis is the most typical and common PM-induced pulmonary fibrosis-related disease, which is mainly induced by occupational exposure to SiO2  dust2,27. SiO2 is often used to develop pulmonary fibrosis animal models by inhalation exposure28-31. In addition to silicon-based PMs, Xu et al. established a pulmonary fibrosis model in mice via multiple intranasal instillations of urban PM2.5, evidenced by reduced pulmonary function, chronic pulmonary inflammation, and otherwise increased histological fibrosis scores23. Jacobsen et al. recognized a dose-dependent increased collagen accumulation in the mouse pulmonary system upon exposure to zinc oxide nanoparticles32. Besides, carbon-based PMs have also been found to be important inducers of pulmonary fibrosis in rats and mice33,34. Overall, PMs are closely implicated in the development of pulmonary fibrosis.

It is a generally accepted mechanism that inhaled PMs in the alveoli interact with alveolar macrophages and then cause pulmonary fibrosis through the activation of pro-inflammatory reactions2. Inhaled PMs enter the alveoli and associate with alveolar macrophages and epithelial cells6. As shown in Figure 1, alveolar macrophages play a crucial role in the pathological process of pulmonary fibrosis. According to previous studies, overall, in the lung injury stage, macrophages are polarized into the M1 state to play a pro-inflammatory and pro-injury role35. And in the lung repair process, M2 macrophages are responsible for the regulation of fibrogenesis, which aggravates the progression of pulmonary fibrosis35,36. M2 macrophages can secrete excess TGF-β to enhance the proliferation and differentiation of lung fibroblasts and thus facilitate the progression of pulmonary fibrosis37. Moreover, a previous study has revealed that PM exposure could trigger epithelial-mesenchymal transition (EMT) in alveolar epithelial cells38. And epithelial cells are also verified to contribute to pulmonary fibrosis via EMT38-40. Persistent chronic inflammation is one of the preconditions for progressive fibrosis41. It has been reported that macrophage-mediated inflammation is vital in forming PM-induced pulmonary fibrosis42. Once PMs cause alveolar macrophage damage, cytokines, such as TGF-β, TNF-α, IL-1β and IL-6 are released from macrophages. These cytokines will further promote more fibroblasts' activation and transformation into myofibroblasts13,43-45. Then accompanied by the deposition of collagen leads to excessive accumulation of extracellular matrix in the alveolus and interstitium, leading to pulmonary fibrosis43.


Figure 1: Inhaled PMs trigger fibroblast activation and fibrosis via cytokine release by alveolar macrophages

Macrophage ferroptosis upon PM exposure

Ferroptosis is, per se, a kind of oxidative stress-induced cell death16. The labile iron pool (LIP) provides active Fe2+ to initiate the Fenton reaction, associated with excess reactive oxygen species (ROS) production and increased sensitization of cells to ferroptosis17. And lipid oxidation (LPO) is a key process and an outcome of ferroptosis46. The generation of LPO involves iron-catalyzed enzymatic (ALOXs) and non-enzymatic (the Fenton chemistry-aided) processes47. Moreover, repressed glutathione peroxidase 4 (GPX4) and reduced glutathione (GSH) account for the initiation of ferroptosis16,48. As a newly defined PCD, ferroptosis was recognized to be implicated in diverse diseases, including neurodegeneration49, cerebro-cardiovascular diseases50, 51 and pulmonary diseases. For example, iron overload, decreased GSH and GPX4 were found in pulmonary tissue in oleic acid-induced acute lung injury (ALI)52. Besides, Ghio et al. found that the iron and ferritin contents in BALF, serum ferritin levels and nonheme iron concentrations were elevated in the rat lung tissue after exposure to cigarette smoke53. This mini review focuses on the role of macrophage ferroptosis in PM-induced pulmonary diseases.

With the increasing environmental pollution problems, the health effects caused by exposure to PMs are considerably drawing people's attention. The development of industry also gave rise to occupational exposure. A growing number of studies suggest that PM exposure causes macrophage ferroptosis11,23,54. The inhaled PMs invade alveoli and attack alveolar macrophages, and the cues of ferroptosis with decreased superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels were observed in mice pulmonary tissues23. Signal transducer and activator of transcription 6 (STAT6) is a key regulator in innate immune response, which mediates direct repression of inflammatory enhancers and regulates activation of alternatively polarization55. Yang et al. found that ALI caused by crystalline silica was reversed by overexpression of STAT6 to suppress ferroptosis via positively regulating SLC7A11 in pulmonary epithelial cells56. Liu et al. reported that quartz particles induced ferroptosis in macrophage cell line RAW 264.7 in vitro and ferroptotic effects such as suppression of GPX4 and accumulation of malondialdehyde (MDA), a lipid peroxidation product in mice lung tissue in vivo7. Since SiO2 is an apparent inducer of pulmonary fibrosis in silicosis, there is also a correlation between ferroptosis and pulmonary fibrosis, and ferroptosis may take part in SiO2-induced pulmonary fibrosis. These findings suggest that ferroptosis is involved in PM-induced lung disorders.

With the widespread applications of nanoproducts, there is an increased risk of exposure to nanoparticles, scilicet nano-scaled PMs6,57. Although 1-2 μm PMs are most pathogenic in the respiratory system21,58, toxicity caused by nano-scaled PMs is worth further study due to the unique properties of nanomaterials. Recently, several pieces of research focused on the ferroptotic cell death caused by nano-scaled PMs. Li et al. found that 2D-layered carbon-based materials graphene oxides (GOs), a type of nano-scaled PM, triggered significant lipid peroxidation in human macrophage THP-1 and mouse alveolar macrophages in vivo. Meanwhile, they also unraveled that the surface oxidation state and carbon radical content of GOs greatly dictated the generation of lipid peroxide in cells54. In another study, they found transition metal dichalcogenides WS2 and MoS2 nanosheets induced macrophages and epithelial cell ferroptosis, and their nano-SAR analysis revealed that surface vacancies of the nanosheets were the real culprit in ferroptosis11. The above studies have unveiled that some nanoparticles could also be considered as nano-scaled ferroptosis inducers and may cause pulmonary fibrosis via ferroptosis. Understanding nano-scaled particle-associated ferroptosis is extremely important for the safety design of nanoproducts. To this end, PMs as the pulmonary fibrosis inducers are also responsible for cell ferroptosis, and it is valuable to perform more in-depth studies to shed light on the connections between alveolar macrophage ferroptosis and pulmonary fibrosis.

The involvement of macrophage ferroptosis in pulmonary fibrosis

Previous studies have indicated that macrophage death plays a vital part in pulmonary fibrosis, and different cell death types give rise to diverse detrimental outcomes12. In recent years, the action of ferroptosis in PM-induced cytotoxicity has attracted research interest. Liu et al. found that SiO2-induced fibroblast activation was obviously suppressed by ferrostatin-1, a specific inhibitor of ferroptosis7. Through a co-culture system of macrophage RAW 264.7 and mouse lung fibroblasts, they recognized that the ferroptotic damage of macrophages caused by PMs triggered the release of inflammatory factors and TGF-β, which in turn induced the activation of fibroblasts7. In addition, ferroptosis also plays an essential role in inflammation59. Li et al. found  WS2 and MoS2 nanosheets induced lung inflammation and promoted cytokine secretion, including lipopolysaccharide-induced CXC chemokine (LIX), TNF-α and IL-1β in bronchoalveolar lavage fluid from exposed mice11. These cytokines, especially TNF-α and IL-1β, were closely related to fibrosis60,61. Disrupted cellular iron homeostasis is a critical cause of ferroptosis15. Ali et al. found that iron accumulation was increased in lung tissue sections of pulmonary fibrosis patients. Their animal experiment also showed that iron accumulation localized predominantly in macrophages, and intranasal treatment with the iron chelator deferoxamine (DFO) could inhibit airway fibrosis and decline in lung function62. These findings suggest that ferroptosis in macrophages has a potential causal correlation to pulmonary fibrosis. Earlier studies have showed that 4-hydroxy-2,3-nonenal (HNE), a major end product of cellular lipid peroxide and a key biological marker of ferroptosis, could further elevate TGF-β1 expression in J774.A1 macrophages63. This circumstantial evidence suggests that macrophage ferroptosis may be an important motivator of fibroblast activation. Furthermore, Li et al. and Tao et al. found that liproxstatin-1, a ferroptosis inhibitor, functioned to remarkably reduce TGF-β expression and collagen accumulation in the idiopathic pulmonary fibrosis animal model64,65. The implications of macrophages in this process needs further exploration. Overall, macrophage ferroptosis contributes to PM-induced pulmonary fibrosis. However, the specific causal relationship between macrophage ferroptosis and pulmonary fibrosis still requires detailed investigation, and the exact mechanisms warrant further studies (Figure 2).


Figure 2: PM-induced macrophage ferroptosis is actively involved in pulmonary fibrosis

Conclusions and Perspectives

In the past views, macrophage damage-associated cytokines, such as TGF-β, TNF-α, IL-1, IL-6 and IL-10, could promote fibroblast proliferation and activation and collagen accumulation, ultimately leading to pulmonary fibrosis. The contributions of macrophage death to pulmonary fibrosis are not clearly understood, which is of great importance for the pathology and therapeutics of PM-associated pulmonary fibrosis. Moreover, the role of the macrophage state in lung fibrosis is very complicated, and there are great controversies over whether a particular phenotype aggravates or improves fibrosis. Although previous studies suggest that a predominant pro-fibrotic M2 priming state is detrimental to pulmonary fibrosis, the role of ferroptosis in macrophage polarization remains to be further explored. In this review, we exploited the contributions of PM-induced ferroptosis to macrophage damage, which then lead to pulmonary fibrosis. In short, PM-induced ferroptotic cell death in macrophages is significantly accountable for pulmonary fibrosis. Ferroptosis-associated inflammation is one of the fundamental ways to promote fibrosis, but more underlying mechanisms remain to be further explored. In fact, in the PM-induced lung injury model, PMs could induce ferroptotic effects not only in macrophages but also in other cell types. Nevertheless, identifying which cell types undergo ferroptosis in pulmonary fibrosis and their contributions to the progress of pulmonary fibrosis remains a challenge. The types of lung cell damage caused by PMs are complex, including apoptosis, necroptosis, pyroptosis and autophagy, and it is valuable to figure out their roles in PM-induced fibrosis. In terms of anti-cellular damage, since ferroptosis contributes to the pathogenesis of pulmonary fibrosis, it is hopeful to prevent and treat PM-induced pulmonary fibrosis via anti-ferroptosis strategies. Nevertheless, as PMs deposited in the lungs are the fundamental initiating factor of fibrosis, preventing inhalation of PMs and developing a method to remove PMs from the lung may represent the basic and essential intervention methods. As an outlook, in future clinical practice, one can try to delay the progression of PM-induced fibrosis by regulating alveolar macrophage ferroptosis and related homeostasis in pulmonary fibrosis patients.

Conflict of Interest

The authors have no conflict of interest to disclose.


  1. Lee YG, Lee PH, Choi SM, et al. Effects of Air Pollutants on Airway Diseases. Int J Environ Res Public Health. 2021; 18(18): 9905.
  2. Weissman DN. Progressive massive fibrosis: An overview of the recent literature. Pharmacol Ther. 2022; 240: 108232.
  3. Thangavel P, Park D, Lee YC. Recent Insights into Particulate Matter (PM2.5)-Mediated Toxicity in Humans: An Overview. Int J Environ Res Public Health. 2022; 19(12): 7511.
  4. Qi Y, Wei S, Chen Y, et al. Intrusion of inhaled exotic ultrafine particles into the knee joint in humans and animals: A risk to the joint and surrounding tissues. Nano Today. 2022.
  5. Qi Y, Wei S, Xin T, et al. Passage of exogeneous fine particles from the lung into the brain in humans and animals. Proc Natl Acad Sci U S A. 2022; 119(26): e2117083119.
  6. Xia T, Zhu Y, Mu L, et al. Pulmonary diseases induced by ambient ultrafine and engineered nanoparticles in twenty-first century. Natl Sci Rev. 2016; 3(4): 416-429.
  7. Liu T, Bao R, Wang Q, et al. SiO2-induced ferroptosis in macrophages promotes the development of pulmonary fibrosis in silicosis models. Toxicol Res (Camb). 2022; 11(1): 42-51.
  8. Wang S, Chen Y, Hong W, et al. Chronic exposure to biomass ambient particulate matter triggers alveolar macrophage polarization and activation in the rat lung. J Cell Mol Med. 2022; 26(4): 1156-1168.
  9. Xu Z, Li Z, Liao Z, et al. PM2.5 induced pulmonary fibrosis in vivo and in vitro. Ecotoxicol Environ Saf. 2019; 171: 112-121.
  10. Hindman B, Ma Q. Carbon nanotubes and crystalline silica stimulate robust ROS production, inflammasome activation, and IL-1beta secretion in macrophages to induce myofibroblast transformation. Arch Toxicol. 2019; 93(4): 887-907.
  11. Xu S, Zheng H, Ma R, et al. Vacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death. Nat Commun. 2020; 11(1): 3484.
  12. Tan S, Chen S. The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis. Int J Mol Sci. 2021; 22(15): 8110.
  13. Joshi GN, Knecht DA. Silica phagocytosis causes apoptosis and necrosis by different temporal and molecular pathways in alveolar macrophages. Apoptosis. 2013; 18(3): 271-285.
  14. Sun Y, Kinsela AS, Waite TD. Elucidation of alveolar macrophage cell response to coal dusts: Role of ferroptosis in pathogenesis of coal workers' pneumoconiosis. Sci Total Environ. 2022; 823: 153727.
  15. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell. 2012; 149(5): 1060-1072.
  16. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nature Chemical Biology. 2014; 10(1): 9-17.
  17. Zhang S, Xin W, Anderson GJ, et al. Double-edge sword roles of iron in driving energy production versus instigating ferroptosis. Cell Death Dis. 2022; 13(1): 40.
  18. Yang Y, Wang Y, Guo L, et al. Interaction between macrophages and ferroptosis. Cell Death Dis. 2022; 13(4): 355.
  19. Qi XM, Luo Y, Song MY, et al. Pneumoconiosis: current status and future prospects. Chin Med J (Engl). 2021; 134(8): 898-907.
  20. Kurth L, Laney AS, Blackley DJ, et al. Prevalence of spirometry-defined airflow obstruction in never-smoking working US coal miners by pneumoconiosis status. Occup Environ Med. 2020; 77(4): 265-267.
  21. Vanka KS, Shukla S, Gomez HM, et al. Understanding the pathogenesis of occupational coal and silica dust-associated lung disease. Eur Respir Rev. 2022; 31(165): 210250.
  22. Tomos I, Dimakopoulou K, Manali ED, et al. Long-term personal air pollution exposure and risk for acute exacerbation of idiopathic pulmonary fibrosis. Environ Health. 2021; 20(1): 99.
  23. Xu M, Wang X, Xu L, et al. Chronic lung inflammation and pulmonary fibrosis after multiple intranasal instillation of PM2.5 in mice. Environ Toxicol. 2021; 36(7): 1434-1446.
  24. Zheng R, Song P, Wu Y, et al. Property-activity relationship between physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome. NanoImpact. 2022; 25: 100380.
  25. Zelko IN, Zhu J, Ritzenthaler JD, et al. Pulmonary hypertension and vascular remodeling in mice exposed to crystalline silica. Respir Res. 2016; 17(1): 160.
  26. Kawanami O, Jiang HX, Mochimaru H, et al. Alveolar fibrosis and capillary alteration in experimental pulmonary silicosis in rats. Am J Respir Crit Care Med. 1995; 151(6): 1946-1955.
  27. Leung CC, Yu IT, Chen W. Silicosis. Lancet. 2012; 379(9830): 2008-2018.
  28. Walters EH, Shukla SD. Silicosis: Pathogenesis and utility of animal models of disease. Allergy. 2021; 76(10): 3241-3242.
  29. Li B, Mu M, Sun Q, et al. A suitable silicosis mouse model was constructed by repeated inhalation of silica dust via nose. Toxicol Lett. 2021; 353: 1-12.
  30. Biswas R, Trout KL, Jessop F, et al. Imipramine blocks acute silicosis in a mouse model. Part Fibre Toxicol. 2017; 14(1): 36.
  31. Chen J, Yao Y, Su X, et al. Comparative RNA-Seq transcriptome analysis on silica induced pulmonary inflammation and fibrosis in mice silicosis model. J Appl Toxicol. 2018; 38(5): 773-782.
  32. Jacobsen NR, Stoeger T, van den Brule S, et al. Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories. Food Chem Toxicol. 2015; 85: 84-95.
  33. Kan Z, Zhao KX, Jiang C, et al. Respiratory exposure to graphene oxide induces pulmonary fibrosis and organ damages in rats involving caspase-1/p38MAPK/TGF-beta1 signaling pathways. Chemosphere. 2022; 303(Pt 3): 135181.
  34. Wu T, Wang X, Chen M, et al. Respiratory exposure to graphene quantum dots causes fibrotic effects on lung, liver and kidney of mice. Food Chem Toxicol. 2022; 163: 112971.
  35. Zhao Y, Hao C, Bao L, et al. Silica particles disorganize the polarization of pulmonary macrophages in mice. Ecotoxicol Environ Saf. 2020; 193: 110364.
  36. Zhao Q, Chen H, Yang T, et al. Direct effects of airborne PM2.5 exposure on macrophage polarizations. Biochim Biophys Acta. 2016; 1860(12): 2835-2843.
  37. Zhang ZQ, Tian HT, Liu H, et al. The role of macrophage-derived TGF-beta1 on SiO2-induced pulmonary fibrosis: A review. Toxicol Ind Health. 2021; 37(4): 240-250.
  38. Cochard M, Ledoux F, Landkocz Y. Atmospheric fine particulate matter and epithelial mesenchymal transition in pulmonary cells: state of the art and critical review of the in vitro studies. J Toxicol Environ Health B Crit Rev. 2020; 23(7): 293-318.
  39. Rout-Pitt N, Farrow N, Parsons D, et al. Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology. Respir Res. 2018; 19(1): 136.
  40. Chen KJ, Li Q, Weng CM, et al. Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis. Biosci Rep. 2018; 38(6): BSR20180445.
  41. Heukels P, Moor CC, von der Thusen JH, et al. Inflammation and immunity in IPF pathogenesis and treatment. Respir Med. 2019; 147: 79-91.
  42. Allard B, Panariti A, Martin JG. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection. Front Immunol. 2018; 9: 1777.
  43. Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004; 55: 395-417.
  44. Li N, Shi F, Wang X, et al. Silica dust exposure induces pulmonary fibrosis through autophagy signaling. Environ Toxicol. 2021; 36(7): 1269-1277.
  45. Zhang J, Yang X, Yang Y, et al. NF-kappaB mediates silica-induced pulmonary inflammation by promoting the release of IL-1beta in macrophages. Environ Toxicol. 2022.
  46. Yang WS, Stockwell BR. Ferrootosis: Death by Lipid Peroxidation. Trends Cell Biol. 2016; 26(3): 165-176.
  47. Toyokuni S, Ito F, Yamashita K, et al. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Free Radic Biol Med. 2017; 108: 610-626.
  48. Shah R, Margison K, Pratt DA. The Potency of Diarylamine Radical-Trapping Antioxidants as Inhibitors of Ferroptosis Underscores the Role of Autoxidation in the Mechanism of Cell Death. Acs Chem Biol. 2017; 12(10): 2538-2545.
  49. Masaldan S, Bush AI, Devos D, et al. Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. 2019; 133: 221-233.
  50. Zhao Z, Wu J, Xu H, et al. XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia-reperfusion injury. Cell Death Dis. 2020; 11(8): 629.
  51. She X, Lan B, Tian H, et al. Cross Talk Between Ferroptosis and Cerebral Ischemia. Front Neurosci. 2020; 14: 776.
  52. Zhou H, Li F, Niu JY, et al. Ferroptosis was involved in the oleic acid-induced acute lung injury in mice. Sheng Li Xue Bao. 2019; 71(5): 689-697.
  53. Ghio AJ, Hilborn ED, Stonehuerner JG, et al. Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect. Am J Respir Crit Care Med. 2008; 178(11): 1130-1138.
  54. Li R, Guiney LM, Chang CH, et al. Surface Oxidation of Graphene Oxide Determines Membrane Damage, Lipid Peroxidation, and Cytotoxicity in Macrophages in a Pulmonary Toxicity Model. ACS Nano. 2018; 12(2): 1390-1402.
  55. Czimmerer Z, Daniel B, Horvath A, et al. The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages. Immunity. 2018; 48(1): 75-90.
  56. Yang Y, Ma Y, Li Q, et al. STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway. Cell Death Dis. 2022; 13(6): 530.
  57. Liu S, Lu Y, Chen W. Bridge knowledge gaps in environmental health and safety for sustainable development of nano-industries. Nano Today. 2018; 23: 11-15.
  58. Nishida C, Yatera K. The Impact of Ambient Environmental and Occupational Pollution on Respiratory Diseases. Int J Environ Res Public Health. 2022; 19(5): 2788.
  59. Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021; 218(6): e20210518.
  60. Chanda D, Otoupalova E, Smith SR, et al. Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med. 2019; 65: 56-69.
  61. Laskin DL, Malaviya R, Laskin JD. Role of Macrophages in Acute Lung Injury and Chronic Fibrosis Induced by Pulmonary Toxicants. Toxicol Sci. 2019; 168(2): 287-301.
  62. Ali MK, Kim RY, Brown AC, et al. Critical role for iron accumulation in the pathogenesis of fibrotic lung disease. J Pathol. 2020; 251(1): 49-62.
  63. Leonarduzzi G, Scavazza A, Biasi F, et al. The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J. 1997; 11(11): 851-857.
  64. Li X, Duan L, Yuan S, et al. Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-beta1. J Inflamm (Lond). 2019; 16: 11.
  65. Tao N, Li K, Liu J, et al. Liproxstatin-1 alleviates bleomycin-induced alveolar epithelial cells injury and mice pulmonary fibrosis via attenuating inflammation, reshaping redox equilibrium, and suppressing ROS/p53/alpha-SMA pathway. Biochem Biophys Res Commun. 2021; 551: 133-139.

Article Info

Article Notes

  • Published on: September 20, 2022


  • Particulate matters
  • Alveolar macrophages
  • Ferroptosis
  • Pulmonary fibrosis


Dr. Bin Shi,
Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China;

Copyright: ©2022 Shi B. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.