Heart failure (HF), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD) frequently coexist and collectively constitute a high-risk multimorbid state characterized by shared pathophysiology, compounded exercise intolerance, frailty, and worse clinical outcomes. These overlapping conditions interact through several mechanisms, including neurohormonal activation, systemic inflammation, oxidative stress, endothelial dysfunction, hemodynamic interactions, and skeletal muscle abnormalities. These mechanisms restrict functional capacity through both central and peripheral pathways. Exercise-based rehabilitation has emerged as an essential nonpharmacological intervention across cardiovascular, renal, and pulmonary medicine and is supported by robust evidence for improvements in exercise capacity and health-related quality of life in single-organ disease populations. However, patients with overlapping cardio-renal-pulmonary impairment remain underrepresented in rehabilitation trials, and evidence for the triple overlap of HF, CKD, and COPD remains particularly scarce. This narrative review synthesizes current evidence on the pathophysiology of cardio-renal-pulmonary multimorbidity and the mechanisms of exercise intolerance. Furthermore, it summarizes functional phenotypes, clinical assessments, and the effects of exercise-based rehabilitation across single-organ and overlapping disease states. Finally, practical implications for individualized exercise prescription, delivery models, and safety monitoring are discussed. We propose a phenotype-guided, function-centered framework for rehabilitation in this complex population and outline key research priorities to strengthen the evidence base for this high-risk, underserved population.

Goblet cell hyperplasia (GCH) is a hallmark of chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality. We investigated the cellular and molecular origins of GCH in COPD using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and in vitro models. We identified "basal-to-goblet transitional cells" (BGTC) which are transcriptionally and physically located between basal and goblet cells and are characterized by expression of clade B serpins. In vitro studies indicate that inflammatory cytokines, including IL-1β, stimulate basal-to-goblet differentiation through a SERPINB3/4 + intermediate and SERPINB3 overexpression induces differentiation of airway basal cells into IL1B -producing inflammatory goblet cells. In addition, we identified a subset of SERPINB4 + "goblet-variant basal cells" from lungs of COPD patients that express goblet cell and inflammatory genes ex vivo. Together, these results indicate clade B serpins contribute to altered epithelial differentiation and inflammatory signaling in COPD and support therapeutic targeting of clade B serpins to reduce GCH.

Severe respiratory viral disease varies widely among individuals and often reflects immunopathology rather than inadequate pathogen control, suggesting that previous immune history can prime the lungs towards disease tolerance. Here we show that nerve- and airway-associated macrophages (NAMs), a subset of interstitial macrophages, expand ephemerally after type 2 inflammation induced by Nippostrongylus brasiliensis. We therefore hypothesized that NAMs acquire epigenetically imprinted trained immunity and tested this using a heterologous challenge model in which mice that were previously infected with N. brasiliensis were challenged 4-6 weeks later with lethal H1N1 influenza. All of the N. brasiliensis-conditioned mice survived, whereas all of the unconditioned controls succumbed by days 5-6. Protection occurred without reduced viral burden or enhanced T cell responses, instead tracking with reduced immunopathology, amplified type 2 cues, increased efferocytosis and accelerated tissue repair. Using NAM-DTR mice, we show that conditioned NAMs are necessary and sufficient for protection: depletion or replacement with unconditioned NAMs abrogated survival, whereas adoptive transfer of conditioned NAMs conferred tolerance without enhancing viral clearance. Genomic analyses implicated an IL-4-STAT6-PPARγ and ARG1 chromatin program that imprints a pro-resolving and reparative NAM state driving tissue repair, type 2 immunity and efferocytosis during lethal respiratory viral infections. Finally, meta-analysis of human lung single-cell atlases from cohorts of healthy individuals and individuals with IPF and COPD revealed context-dependent NAM-like repair programs. These findings establish local trained immunity in lung-resident macrophages as a mechanism of disease tolerance and a therapeutic entry point for severe inflammatory respiratory infections.