Bridging Bench to the Bedside: The Imperative of Preclinical and Translational Research in Pulmonary Medicine

Elizabeth F. Redente, PhD, ATSF

Satish K. Madala, PhD

Despite decades of clinical advancement, many acute, chronic, and progressive lung diseases, such as acute lung injury (ALI), idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), and asthma, remain incurable with limited therapeutic options and high morbidity and mortality. Collectively, asthma, IPF, ALI, and LAM impose an annual health care burden exceeding US$100 billion worldwide, reflecting high hospitalization and treatment costs and underscoring the urgent need for basic and translational research to develop effective therapies that reduce morbidity, mortality, and economic impact. The pathophysiology of these diseases is highly complex, driven by the interplay of aging, environmental exposures, genetic susceptibility, cellular heterogeneity, dynamic tissue remodeling, and immune dysregulation. Therefore, it is imperative to investigate the mechanistic underpinnings of disease pathobiology beyond clinical observations and patient-based studies alone. In this context, preclinical and translational research using advanced in vitro cell and ex vivo tissue systems, animal models, and multiomics technologies serves not merely as a complementary approach but rather the essential foundation for translating fundamental discoveries into novel clinical interventions.

This issue of Seminars in Respiratory and Critical Care Medicine brings together a collection of articles that collectively underscore the indispensable role of basic and translational science in shaping the future of pulmonary medicine. From dissecting the molecular underpinnings of fibroblast activation in IPF to unraveling the immune-regulatory functions of T cells and macrophages in lung injury and repair in basic translational research.

Preclinical models of pulmonary fibrosis are indispensable for dissecting the cellular and molecular mechanisms driving fibrotic lung remodeling, enabling the identification and validation of therapeutic targets that cannot be fully explored through patient studies alone. The bleomycin-induced lung injury model remains the most widely used and well-characterized experimental system for studying pulmonary fibrosis. As reviewed by Brazee et al, this model offers a reproducible framework to investigate the temporal progression of fibrosis from acute inflammation to fibroproliferation followed by spontaneous resolution.[1] While it does not fully recapitulate the histopathological hallmarks of IPF, such as honeycomb cysts and fibroblastic foci, it has nonetheless been instrumental in the preclinical validation of interstitial lung diseases' FDA-approved therapies pirfenidone and nintedanib. Importantly, refinements to the bleomycin model, such as repetitive dosing, use of aged mice, targeted genetic mutations, and combination injury approaches, have enhanced its translational relevance. These adaptations allow researchers to mimic persistent and progressive fibrosis, better reflecting the clinical trajectory of IPF. Moreover, the bleomycin model's flexibility enables interrogation of the time after injury, sex, strain, microbiome, and environmental influences on disease susceptibility and therapeutic response. It is only in understanding and capitalizing on these insights that will allow for better therapeutic development and the identification of novel disease-based biomarkers as highlighted by Schott et al.[2] Additionally, utilizing the correct in vivo models remains critical for developing personalized treatment strategies and for understanding disease heterogeneity.

Singh et al provide a comprehensive analysis of fibroblast heterogeneity and activation in pulmonary fibrosis.[3] Their work highlights the diverse cellular origins of myofibroblasts, including resident alveolar fibroblasts, and the transcriptional programs that govern their differentiation and persistence during fibrosis. The identification of key regulators, such as TGF-β, PDGF, Wnt ligands, and transcription factors like SMADs, STATs, WT1, and Sox9, offers promising opportunities as therapeutic targets to halt or reverse the profibrotic pathogenesis associated with these critical cells. Additionally, these findings underscore the value of state-of-the-art technologies, including lineage tracing, single-cell RNA sequencing, and spatial transcriptomics, which have allowed researchers to follow and determine mesenchymal cell fate decisions, differentiation pathways, and intercellular communication within the fibrotic niche. Such technologies, when applied to animal models and in vitro human cells and ex vivo human tissue samples, allow research to bridge the gap between molecular discovery and clinical application, enabling the development of targeted antifibrotic therapies.

The complexity of the immune system and its role in pulmonary diseases has been a challenge to study, with exact homologs of human immune cell populations not always being present within murine lungs. However, the importance and contribution of the immune system to every stage of pulmonary disease: Initiation, development, progression, and eventual resolution cannot be underestimated. The article by Pastore et al delves into the immunoregulatory functions of T regulatory cells (Tregs) in airway and ILDs.[4] Their work reveals how Tregs adapt to microenvironmental cues, acquiring phenotypes that either suppress inflammation or contribute to pathogenic remodeling. In asthma, for instance, Tregs can be skewed toward a Th2-like profile, undermining their suppressive capacity and exacerbating disease. Aging, hormonal changes, and genetic polymorphisms further modulate Treg function, highlighting the need for age- and sex-specific therapeutic approaches. Complementing this, Bersie and McCubbrey discuss and explore the heterogeneity of lung phagocytes and their role in clearing apoptotic cells during a process known as efferocytosis.[5] Efficient efferocytosis by alveolar macrophages, interstitial macrophages, dendritic cells, epithelial cells, and fibroblasts is critical for resolving inflammation and promoting tissue repair. Defective clearance of apoptotic cells has been implicated in a range of pulmonary diseases, including chronic obstructive pulmonary disorder (COPD), asthma, cystic fibrosis, and acute respiratory distress syndrome (ARDS). Understanding the molecular and cellular mechanisms that regulate efferocytosis may offer a new avenue for therapeutic intervention aimed at restoring immune balance and preventing maladaptive repair.

Fortier et al take these concepts one step further by challenging the prevailing paradigm of fibrosis research and advocating for a shift from the development of therapies that suppress profibrotic drivers to those that restore endogenous resolution pathways.[6] Drawing parallels to the evolution of cancer therapy (from targeting oncogenes to reactivating tumor suppressors), they propose that initiating fibrosis resolution should be a central therapeutic objective. Utilizing the bleomycin animal model of fibrosis that undergoes spontaneous fibrosis resolution, as discussed above, offers a unique opportunity to identify “resolvers” or molecules and pathways that are capable of reversing scarring and restoring tissue homeostasis. Among these, they have identified cyclic AMP (cAMP) and its downstream effectors as potent antifibrotic mediators, capable of modulating fibroblast phenotype, promoting apoptosis, and enhancing epithelial repair. Excitingly, Nerandomalist, which works through this mechanism by increasing cAMP, elegantly demonstrating this basic-translational research approach, is the newest therapeutic for IPF to be FDA approved in 11 years. The pleiotropic nature of resolvers, such as cAMP, which simultaneously impact multiple cell types and signaling networks, makes them attractive candidates for therapeutic development. Importantly, testing these agents in models of established fibrosis (for example, the repetitive non-resolving bleomycin model, or in aged animals) rather than during disease initiation, aligns more closely with the clinical reality faced by patients and clinicians and aids in better and more accurate therapeutic development.

Single-cell technologies are critical for uncovering the cellular heterogeneity, molecular signatures, and lineage origins of abnormal smooth muscle-like cells in LAM, thereby revealing key pathogenic pathways and therapeutic targets. Yu and colleagues provide a compelling example of how combining multiomics technologies, including single-cell RNA sequencing, ATAC-seq, and spatial transcriptomics, can accelerate biomarker discovery and therapeutic development in LAM.[7] Their identification of LAMCORE cells and uterine-derived transcriptional signatures has reshaped our understanding of disease origin and progression. Moreover, the integration of bioinformatics with experimental validation has led to the development of clinical prediction models and novel drug screening platforms. Such translational efforts exemplify the power of interdisciplinary collaboration, combining computational biology, molecular genetics, and clinical insight to drive this basic-translational innovation. They also highlight the importance of patient-derived models, real-world data, and longitudinal cohort studies in validating therapeutic targets and informing clinical decision-making.

The articles in this Issue collectively affirm that preclinical and translational research is not ancillary to clinical progress but rather integral to it. Cell culture systems, animal models, and multiomics technologies provide the mechanistic clarity and experimental control necessary to unravel the complexities of pulmonary diseases. They enable hypothesis-driven inquiry, therapeutic testing, and biomarker development in ways that are simply not feasible or often ethical in human subjects alone. As we continue to confront the challenges of chronic lung disease, emerging pathogens, and aging populations, the need for robust, reproducible, and clinically relevant preclinical models has never been greater. By investing in basic science, embracing technological innovation, and fostering cross-disciplinary collaboration, we can transform our understanding of pulmonary pathophysiology and the development of novel precision medicine for respiratory diseases.

Publikationsverlauf

Artikel online veröffentlicht:
13. November 2025

• References

• 1 Brazee P, Allen N, Knipe R, Redente EF, Le Saux CJ. Peeling back the layers of the bleomycin model of lung fibrosis: lessons learned, Factors to Consider, and Future Directions. Semin Respir Crit Care Med 2025; 46 (04) 330-346
• 2 Schott CA, Mohning MP, Cooley JC. Emerging concepts in therapeutic interventions for idiopathic pulmonary fibrosis. Semin Respir Crit Care Med 2025; 46 (04) 347-365
• 3 Singh P, Edjah S, Shi W, Madala SK. Emerging concepts in fibroblast biology and progressive pulmonary fibrosis. Semin Respir Crit Care Med 2025; 46 (04) 322-329
• 4 Pastore CF, Stadler BD, Sperling AI, Velez TE. T regulatory mechanisms in airway and interstitial lung disease. Semin Respir Crit Care Med 2025; 46 (04) 378-392
• 5 Bersie SM, McCubbrey AL. Heterogeneity of lung phagocytes and clearance of apoptotic cells in lung injury and repair. Semin Respir Crit Care Med 2025; 46 (04) 311-321
• 6 Fortier SM, Redente EF, Peters-Golden M. Reimagining fibrosis research, outcomes, and therapeutics through the lens of resolution. Semin Respir Crit Care Med 2025; 46 (04) 298-310
• 7 Yu JJ, Gupta N, Guo M, Olatoke T, Xu Y. Emerging concepts in pathogenesis, multiomics applications, and clinical research in lymphangioleiomyomatosis. Semin Respir Crit Care Med 2025; 46 (04) 366-377