{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:27:42Z","timestamp":1786955262552,"version":"build-2736575974"},"reference-count":118,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In the current paper, pulmonary emphysema is hypothesized to emerge from a nonlinear breakdown of cooperation across two tightly coupled systems: the extracellular matrix (ECM) crosslink network and the cellular populations responsible for its maintenance. To formalize this concept, we construct a game-theoretic model that unifies the mechanical failure, inflammatory changes, and percolation-driven tissue collapse that are recognized features of the disease. At the ECM level, elastin and collagen crosslinks are modeled as players in an iterated Prisoner\u2019s Dilemma, where cooperation corresponds to maintaining structural integrity, and defection corresponds to rupture under mechanical stress. At the cellular level, fibroblasts, macrophages, and neutrophils engage in a parallel strategic game in which repair reflects cooperative activity, and protease- or oxidant-producing phenotypes are indicative of defection. These parallel games are coupled through bidirectional payoff modulation, generating a dynamical system with bistability, tipping points, and runaway positive feedback. As the fraction of intact crosslinks falls below a critical percolation threshold, global network connectivity collapses and lung function drops precipitously. This framework explains the characteristic features of pulmonary emphysema, including spatial heterogeneity, abrupt acceleration, and irreversibility as emergent properties of coupled cooperation\u2013defection dynamics, and identifies new leverage points for stabilizing cooperation and preventing catastrophic network failure in early disease. In support of this hypothesis, we present previously published studies from our laboratory involving measurements of elastin-specific desmosine crosslinks in human postmortem emphysematous lungs showing a marked increase in tissue crosslink density at the early stage of the disease, and accelerating loss of these crosslinks as airspace enlargement progresses, consistent with initial cooperation followed by defection. This conceptual framework is then applied to the poorly understood lung disease, Combined Pulmonary Fibrosis and Emphysema, to provide a potential mechanism for its pathogenesis.<\/jats:p>","DOI":"10.3390\/cells15161470","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:05:41Z","timestamp":1786953941000},"page":"1470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cooperation, Defection, and Collapse: A Multiscale Game Theory Framework for Emphysema Progression"],"prefix":"10.3390","volume":"15","author":[{"given":"Jerome","family":"Cantor","sequence":"first","affiliation":[{"name":"School of Pharmacy and Applied Health Sciences, St John\u2019s University, Queens, NY 11439, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1002\/path.5364","article-title":"Recent advances in chronic obstructive pulmonary disease pathogenesis: From disease mechanisms to precision medicine","volume":"250","author":"Brandsma","year":"2020","journal-title":"J. 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