Hernán F. Peñaloza, Atish Gheware, Ananya Gupta, Donovan Watza, Anupam Kumari, Shekina Gonzalez-Ferrer, Zeyu Xiong, Xingan Wang, Gregory A. Gibson, Pooja Bhojraj, Rick van der Geest, Jae-Sung Kim, Bo‐Ram Jin, Mélia Magnen, William G. Bain, Mohammadreza Tabary, Liwen Zhang, Arpad Somogy, Tomasz W. Kamiński, Prithu Sundd, Kyunghee Choi, Anuradha Ray, Prabir Ray, Rama K. Mallampalli, Sébastien Gingras, Matthew R. Rosengart, Mark R. Looney, Jonathan K. Alder, Jaehyung Cho, Claudette M. St. Croix, Janet S. Lee
An early event after lung injury is extracellular matrix (ECM) remodeling and the formation of a provisional matrix. While megakaryocytes and platelets (Mgk/plt) play important roles in hemostasis, their impact on the matrix in lung injury is not fully understood. Using lung intravital microscopy, 3D large area scanning with multiphoton confocal hybrid imaging, and label-free quantitative proteomics, the matricellular protein thrombospondin-1 (TSP1) arising from Mgk/plt protects the lung from alveolar injury. Mgk/plt cell-specific Thbs1 knockout (cKO) mice show increased alveolar barrier disruption with exaggerated neutrophil-mediated injury. The cKO mice exhibit striking extracellular matrix re-organization with reduction in basement membrane matrix protein COL6A1 after injury. Moreover, cKO mice increase Mgk numbers to regions of fibrillar collagen deposition and alveolar leak. Our findings indicate Mgk/plt-derived TSP1 represents a key mechanism of matrix stabilization by protecting the basement membrane from neutrophil-mediated proteolytic damage, regulating injury severity and Mgk numbers at the alveolar interface. An early event after lung injury is extracellular matrix remodelling. Here, the authors show that thrombospondin-1 (TSP1) from megakaryocytes/platelets protects the lung’s extracellular matrix, particularly basement protein COL6. Mice without TSP1 had greater lung damage and neutrophil activity, showing TSP1 reduces injury severity.