Refractory Lung Diseases: From Cellular Structures, Molecular Mechanisms to Therapeutic Strategies

Abstract

Refractory lung diseases (RLDs) encompass a spectrum of progressive pulmonary disorders, including acute respiratory distress syndrome (ARDS), bronchopulmonary dysplasia (BPD), and idiopathic pulmonary fibrosis (IPF). These conditions are defined by poor responsiveness to current therapeutic interventions and pose substantial clinical challenges, primarily due to their high morbidity and mortality rates. This review synthesizes the current understanding of the molecular mechanisms underlying RLDs and explores promising therapeutic strategies. A core feature of RLD pathogenesis is the disruption of alveolar microenvironmental homeostasis, which triggers a bidirectional vicious cycle between structural damage and disease progression. This homeostatic collapse is driven by interconnected pathological networks—including oxidative stress coupled with mitochondrial dysfunction, inflammatory immune dysregulation, and mechanical stress-induced extracellular matrix (ECM) remodeling—all of which are elaborated in this review. Collectively, these pathological processes contribute to therapeutic resistance. Based on these mechanistic insights, potential therapeutic approaches are discussed, such as antioxidant therapies (e.g., the mitochondria-targeted antioxidant Mitoquinone mesylate [MitoQ]) and antifibrotic agents (e.g., pirfenidone, nintedanib, as well as emerging strategies targeting Wnt pathway modulation). Additionally, the critical significance of early diagnosis and personalized precision medicine is emphasized. Future research should focus on a deeper characterization of the dynamic alterations within the alveolar microenvironment under pathological conditions, with the aim of developing more precise diagnostic tools and targeted therapeutic strategies. Ultimately, the therapeutic goal for RLDs should shift from mere symptom management to achieving pathological reversal.

Keywords

alveolar microenvironment homeostasis / antifibrotic therapy / antioxidant therapy / refractory lung diseases (RLDs)

References

[1] GBD 2019 Chronic Respiratory Diseases Collaborators, “Global Burden of Chronic Respiratory Diseases and Risk Factors, 1990–2019: An Update From the Global Burden of Disease Study 2019,” eClinicalMedicine 59 (2023): 101936.

[2] G. Raghu, M. Remy-Jardin, L. Richeldi, et al., “Idiopathic Pulmonary Fibrosis (An Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline,” American Journal of Respiratory and Critical Care Medicine 205, no. 9 (2022): e18–e47.

[3] P. J. Moos, J. R. Cheminant, S. Cowman, et al., “Spatial and Phenotypic Heterogeneity of Resident and Monocyte-Derived Macrophages During Inflammatory Exacerbations Leading to Pulmonary Fibrosis,” Frontiers in Immunology 15 (2024): 1425466.

[4] A. J. Ma, C. Z Wei, M. L. Huang, et al., “Mechanism of Airway Pressure Release Ventilation in Alleviating Pulmonary Inflammation in ARDS via Regulation of the ITGB4-Related Pathway (In Chinese),” Chinese Journal of New Clinical Medicine 17, no. 2 (2024): 128–137.

[5] J. F. Song, “Emphasizing Basic and Clinical Research on Acute Respiratory Distress Syndrome to Explore Novel Diagnostic and Therapeutic Strategies (In Chinese),” Chinese Journal of Emergency Medicine 33, no. 8 (2024): 1059–1062.

[6] S. Rius-Pérez, “P53 at the Crossroad Between Mitochondrial Reactive Oxygen Species and Necroptosis,” Free Radical Biology and Medicine 207 (2023): 183–193.

[7] C. Yao, X. Guan, G. Carraro, et al., “Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis,” American Journal of Respiratory and Critical Care Medicine 203, no. 6 (2021): 707–717.

[8] D. Zhou, K. Yang, L. Chen, et al., “Macrophage Polarization and Function: New Prospects for Fibrotic Disease,” Immunology & Cell Biology 95, no. 10 (2017): 864–869.

[9] X. Meng, G. Cui, and G. Peng, “Lung Development and Regeneration: Newly Defined Cell Types and Progenitor Status,” Cell Regeneration 12, no. 1 (2023): 5.

[10] E. R. Weibel, “Lung Morphometry: The Link Between Structure and Function,” Cell and Tissue Research 367, no. 3 (2017): 413–426.

[11] J. Chen, Z. Chen, T. Narasaraju, N. Jin, and L. Liu, “Isolation of Highly Pure Alveolar Epithelial Type I and Type II Cells From Rat Lungs,” Laboratory Investigation 84, no. 6 (2004): 727–735.

[12] C. E. Barkauskas, M. J. Cronce, C. R. Rackley, et al., “Type 2 Alveolar Cells Are Stem Cells in Adult Lung,” Journal of Clinical Investigation 123, no. 7 (2013): 3025–3036.

[13] R. Jain, C. E. Barkauskas, N. Takeda, et al., “Plasticity of Hopx+Type I Alveolar Cells to Regenerate Type II Cells in the Lung,” Nature Communications 6, no. 1 (2015): 6727.

[14] E. D. Crandall and M. A. Matthay, “Alveolar Epithelial Transport. Basic Science to Clinical Medicine,” American Journal of Respiratory and Critical Care Medicine 163, no. 4 (2001): 1021–1029.

[15] J. Liu and Z. C. Feng, “Application and Research Progress of Pulmonary Surfactant (In Chinese),” Chinese Journal of Preventive Medicine 12, no. 5 (2009): 391–394.

[16] X. Z. Song, “The Role of Lamellar Bodies in the Formation of the Skin Permeability Barrier (In Chinese),” Chinese Journal of Dermatology 51, no. 2 (2018): 163–165.

[17] J. Pérez-Gil, “Lipid-Protein Interactions of Hydrophobic Proteins SP-B and SP-C in Lung Surfactant Assembly and Dynamics,” Pediatric Pathology & Molecular Medicine 20, no. 6 (2001): 445–469.

[18] A. N. Nabhan, D. G. Brownfield, P. B. Harbury, M. A. Krasnow, and T. J. Desai, “Single-Cell Wnt Signaling Niches Maintain Stemness of Alveolar Type 2 Cells,” Science 359, no. 6380 (2018): 1118–1123.

[19] R. Timpl and J. C. Brown, “Supramolecular Assembly of Basement Membranes,” BioEssays 18, no. 2 (1996): 123–132.

[20] J. Kruegel and N. Miosge, “Basement Membrane Components Are Key Players in Specialized Extracellular Matrices,” Cellular and Molecular Life Sciences 67, no. 17 (2010): 2879–2895.

[21] M. Raftopoulou and A. Hall, “Cell Migration: Rho GTPases Lead the Way,” Developmental Biology 265, no. 1 (2004): 23–32.

[22] A. J. Russell, E. F. Fincher, L. Millman, et al., “Alpha 6 Beta 4 Integrin Regulates Keratinocyte Chemotaxis Through Differential GTPase Activation and Antagonism of Alpha 3 Beta 1 Integrin,” Journal of Cell Science 116, no. 17 (2003): 3543–3556.

[23] A. Fuchs and E. R. Weibel, “Morphometric Study of the Distribution of a Specific Cytoplasmatic Organoid in the Rat’s Endothelial Cells,” Zeitschrift fur Zellforschung und mikroskopische Anatomie 73, no. 1 (1966): 1–9, PMID: 389332.

[24] E. R. Weibel, “Fifty Years of Weibel-Palade Bodies: The Discovery and Early History of an Enigmatic Organelle of Endothelial Cells,” Journal of Thrombosis and Haemostasis 10, no. 6 (2012): 979–984.

[25] S. Edamana, F. H. Login, S. Yamada, T.-H. Kwon, and L. N. Nejsum, “Aquaporin Water Channels as Regulators of Cell-Cell Adhesion Proteins,” American Journal of Physiology Cell Physiology 320, no. 5 (2021): C771–C777.

[26] H. N. Yang, D. Lyu, L. Wang, et al., “Functions of Key Genes Involved in TGF-β/Smad Signaling Pathway in Progression of Pulmonary Fibrosis,” Journal of Environment and Occupational Medicine 39, no. 7 (2022): 745–751.

[27] A. T. Garrison, R. E. Bignold, X. Wu, and J. R. Johnson, “Pericytes: The Lung-Forgotten Cell Type,” Frontiers in Physiology 14 (2023): 1150028.

[28] D. J. Zheng, M. Abou Taka, and B. Heit, “Role of Apoptotic Cell Clearance in Pneumonia and Inflammatory Lung Disease,” Pathogens 10, no. 2 (2021): 134.

[29] C. C. W. Hsia, D. M. Hyde, and E. R. Weibel, “Lung Structure and the Intrinsic Challenges of Gas Exchange,” Comprehensive Physiology 6, no. 2 (2016): 827–895.

[30] J. B. West, K. Tsukimoto, O. Mathieu-Costello, and R. Prediletto, “Stress Failure in Pulmonary Capillaries,” Journal of Applied Physiology 70, no. 4 (1991): 1731–1742.

[31] K. Tsukimoto, O. Mathieu-Costello, R. Prediletto, A. R. Elliott, and J. B. West, “Ultrastructural Appearances of Pulmonary Capillaries at High Transmural Pressures,” Journal of Applied Physiology 71, no. 2 (1991): 573–582.

[32] J. B. West, “Invited Review: Pulmonary Capillary Stress Failure,” Journal of Applied Physiology 89, no. 6 (2000): 2483–2489.

[33] J. Liekkinen, A. Olżyńska, L. Cwiklik, J. Bernardino de la Serna, I. Vattulainen, and M. Javanainen, “Surfactant Proteins SP-B and SP-C in Pulmonary Surfactant Monolayers: Physical Properties Controlled by Specific Protein-Lipid Interactions,” Langmuir 39, no. 12 (2023): 4338–4350.

[34] M. A. Matthay, R. L. Zemans, G. A. Zimmerman, et al., “Acute Respiratory Distress Syndrome,” Nature Reviews Disease Primers 5, no. 1 (2019): 18.

[35] B. J. Stoll, N. I. Hansen, E. F. Bell, et al., “Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network,” Pediatrics 126, no. 3 (2010): 443–456.

[36] E. M. Dunican, B. M. Elicker, D. S. Gierada, et al., “Mucus Plugs in Patients With Asthma Linked to Eosinophilia and Airflow Obstruction,” Journal of Clinical Investigation 128, no. 3 (2018): 997–1009.

[37] T. Narasaraju, E. Yang, R. P. Samy, et al., “Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis,” American Journal Of Pathology 179, no. 1 (2011): 199–210.

[38] B. N. Porto and R. T. Stein, “Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good Thing?,” Frontiers in Immunology 7 (2016): 311.

[39] T. Salaets, J. Richter, P. Brady, et al., “Transcriptome Analysis of the Preterm Rabbit Lung After Seven Days of Hyperoxic Exposure,” PLoS One 10, no. 8 (2015): e0136569.

[40] L. Amarelle, L. Quintela, J. Hurtado, and L. Malacrida, “Hyperoxia and Lungs: What We Have Learned From Animal Models,” Frontiers of Medicine 8 (2021): 606678.

[41] M. Perez, M. E. Robbins, C. Revhaug, and O. D. Saugstad, “Oxygen Radical Disease in the Newborn, Revisited: Oxidative Stress and Disease in the Newborn Period,” Free Radical Biology and Medicine 142 (2019): 61–72.

[42] T. Xie and G. P. Li, “Research Progress on Oxidative Stress and Airway Mucus Hypersecretion in Bronchial Asthma (In Chinese),” Chinese Journal of Asthma (Electronic Edition) 7, no. 1 (2013): 49–52.

[43] Z. Xia, X. Duan, S. Tao, et al., “Pollution Level, Inhalation Exposure and Lung Cancer Risk of Ambient Atmospheric Polycyclic Aromatic Hydrocarbons (PAHs) in Taiyuan, China,” Environmental Pollution 173 (2013): 150–156.

[44] P. Zhao and J. Gao, “Role of Nrf2/Keap1/ARE Signaling Pathway in Respiratory Diseases,” Chinese Pharmacological Bulletin 31, no. 11 (2015): 1488–1492.

[45] S. G. Wendell, C. Baffi, and F. Holguin, “Fatty Acids, Inflammation, and Asthma,” Journal of Allergy and Clinical Immunology 133, no. 5 (2014): 1255–1264.

[46] N. Tan, B. L. Li, A. Aili, and X. J. Zhao, “Research Progress on the Mitochondrial-Targeted Antioxidant MitoQ (In Chinese),” Journal of Agricultural Biotechnology 32, no. 6 (2024): 1432–1439.

[47] M. Cen, W. Ouyang, W. Zhang, et al., “MitoQ Protects Against Hyperpermeability of Endothelium Barrier in Acute Lung Injury via a Nrf2-Dependent Mechanism,” Redox Biology 41 (2021): 101936.

[48] Y. Zhu and J. Yang, “Effect and Mechanism of IL-6 Induced by M2 Macrophages on the Lung Fibroblasts Activation,” Acta Pharmaceutica Sinica 55, no. 5 (2020): 892–897.

[49] Y. T. Yeung, F. Aziz, A. Guerrero-Castilla, and S. Arguelles, “Signaling Pathways in Inflammation and Anti-Inflammatory Therapies,” Current Pharmaceutical Design 24, no. 14 (2018): 1449–1484.

[50] Y. Zhu, X. Peng, S. Fan, Y. Sun, and X. Zhang, “Research Progress on the Role of Inflammation and Oxidative Stress in Acute Lung Injury,” Hans Journal of Biomedicine 14, no. 1 (2024): 48–55.

[51] X. Bai, C. Wang, P. Zhao, and Y. Li, “The Role and Molecular Mechanism of Pyroptosis in Bronchiolitis Obliterans (In Chinese),” Chinese Journal of Pediatrics 61, no. 4 (2023): 373–376.

[52] H. Kasai, J. T. Allen, R. M. Mason, T. Kamimura, and Z. Zhang, “TGF-Β1 Induces Human Alveolar Epithelial to Mesenchymal Cell Transition (EMT),” Respiratory Research 6, no. 1 (2005): 56.

[53] S. Dupont, L. Morsut, M. Aragona, et al., “Role of YAP/TAZ in Mechanotransduction,” Nature 474, no. 7350 (2011): 179–183.

[54] R. LaCanna, D. Liccardo, P. Zhang, et al., “Yap/Taz Regulate Alveolar Regeneration and Resolution of Lung Inflammation,” Journal of Clinical Investigation 129, no. 5 (2019): 2107–2122.

[55] J. Q. Wang, L. S. Huang, H. F. Yu, et al., “Role of Hippo-YAP/TAZ Signaling Pathway in Organ Fibrosis (In Chinese),” Journal of Central South University 49, no. 9 (2024): 1509–1516.

[56] G. Hansmann, H. Sallmon, C. C. Roehr, S. Kourembanas, E. D. Austin, and M. Koestenberger, “Pulmonary Hypertension in Bronchopulmonary Dysplasia,” Pediatric Research 89, no. 3 (2021): 446–455.

[57] J. E. Mahoney, M. Mori, A. D. Szymaniak, X. Varelas, and W. V. Cardoso, “The Hippo Pathway Effector Yap Controls Patterning and Differentiation of Airway Epithelial Progenitors,” Developmental Cell 30, no. 2 (2014): 137–150.

[58] C. Chung, T. Kim, M. Kim, et al., “Hippo-Foxa2 Signaling Pathway Plays a Role in Peripheral Lung Maturation and Surfactant Homeostasis,” Proceedings of the National Academy of Sciences of the United States of America 110, no. 19 (2013): 7732–7737.

[59] A. W. Lange, A. Sridharan, Y. Xu, B. R. Stripp, A.-K. Perl, and J. A. Whitsett, “Hippo/Yap Signaling Controls Epithelial Progenitor Cell Proliferation and Differentiation in the Embryonic and Adult Lung,” Journal of Molecular Cell Biology 7, no. 1 (2015): 35–47.

[60] P. B. Dieffenbach, C. M. Haeger, A. M. F. Coronata, et al., “Arterial Stiffness Induces Remodeling Phenotypes in Pulmonary Artery Smooth Muscle Cells via YAP/TAZ-Mediated Repression of Cyclooxygenase-2,” American Journal of Physiology - Lung Cellular and Molecular Physiology 313, no. 3 (2017): L628–L647.

[61] J. Fan, Z. Khanzada, and Y. Xu, “Mechanisms Underlying Muscle-Related Diseases and Aging: Insights Into Pathophysiology and Therapeutic Strategies,” Muscles 4, no. 3 (2025): 26.

[62] T. Zhao, J. Fan, A. Abu-Zaid, S. K. Burley, and X. F. Steven Zheng, “Nuclear mTOR Signaling Orchestrates Transcriptional Programs Underlying Cellular Growth and Metabolism,” Cells 13, no. 9 (2024): 781.

[63] J. Fan, Z. Yuan, S. K. Burley, S. K. Libutti, and X. F. Steven Zheng, “Amino Acids Control Blood Glucose Levels Through mTOR Signaling,” European Journal of Cell Biology 101, no. 3 (2022): 151240.

[64] H. Y. Jeon, J. Choi, L. Kraaier, et al., “Airway Secretory Cell Fate Conversion via YAP-mTORC1-Dependent Essential Amino Acid Metabolism,” EMBO Journal 41, no. 8 (2022): e109365.

[65] M. P. Murphy and R. A. Smith, “Drug Delivery to Mitochondria: The Key to Mitochondrial Medicine,” Advanced Drug Delivery Reviews 41, no. 2 (2000): 235–250.

[66] M. P. Murphy, “Development of Lipophilic Cations as Therapies for Disorders due to Mitochondrial Dysfunction,” Expert Opinion on Biological Therapy 1, no. 5 (2001): 753–764.

[67] G. F. Rushworth and I. L. Megson, “Existing and Potential Therapeutic Uses for N-Acetylcysteine: The Need for Conversion to Intracellular Glutathione for Antioxidant Benefits,” Pharmacology & Therapeutics 141, no. 2 (2014): 150–159.

[68] A. J. Podolanczuk, I. Noth, and G. Raghu, “Idiopathic Pulmonary Fibrosis: Prime Time for a Precision-Based Approach to Treatment With N-Acetylcysteine,” European Respiratory Journal 57, no. 1 (2021): 2003551.

[69] D. Mokra, J. Mokry, R. Barosova, and J. Hanusrichterova, “Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases,” Antioxidants 12, no. 9 (2023): 1713.

[70] R. A. J. Smith, R. C. Hartley, H. M. Cochemé, and M. P. Murphy, “Mitochondrial Pharmacology,” Trends in Pharmacological Sciences 33, no. 6 (2012): 341–352.

[71] M. Punetha, S. Saini, S. Chaudhary, et al., “Mitochondria-Targeted Antioxidant MitoQ Ameliorates ROS Production and Improves Cell Viability in Cryopreserved Buffalo Fibroblasts,” Tissue and Cell 82, no. 2023 (2023): 102067.

[72] Y. Tian, J. Lv, Z. Su, et al., “LRRK2 Plays Essential Roles in Maintaining Lung Homeostasis and Preventing the Development of Pulmonary Fibrosis,” Proceedings of the National Academy of Sciences of the United States of America 118, no. 35 (2021): e2106685118.

[73] F. Zhu and H. Feng, “Relationship Between WNT/β-Catenin Transduction Signaling Pathway and Pulmonary Fibrosis,” Academic Journal of Chinese PLA Medical School 36, no. 10 (2015): 1045–1047.

[74] W. Gan, K. Huang, Z. Lv, et al., “Comparison of In-Vitro Anti-Fibrotic Effects of Pirfenidone and Nintedanib,” Idiopathic Interstitial Pneumonias 54 (2019): PA1282.

[75] M. Königshoff, N. Balsara, E.-M. Pfaff, et al., “Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis,” PLoS One 3, no. 5 (2008): e2142.

[76] S. Shen, P. Wang, P. Wu, et al., “CasRx-Based Wnt Activation Promotes Alveolar Regeneration While Ameliorating Pulmonary Fibrosis in a Mouse Model of Lung Injury,” Molecular Therapy 32, no. 11 (2024): 3974–3989.

[77] X. Pan, L. Wang, J. Yang, et al., “TRβ Activation Confers AT2-to-AT1 Cell Differentiation and Anti-Fibrosis During Lung Repair via KLF2 and CEBPA,” Nature Communications 15, no. 1 (2024): 8672.

[78] F. Bühling, C. Röcken, F. Brasch, et al., “Pivotal Role of Cathepsin K in Lung Fibrosis,” American Journal Of Pathology 164, no. 6 (2004): 2203–2216.

RIGHTS & PERMISSIONS

2026 The Author(s). Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children's Hospital of Chongqing Medical University.