Pulmonary infections are characterized by neutrophil recruitment into the lung driven by chemokine ligands of CXCR2, which is expressed on neutrophils, but also present in non-hematopoietic lung cells, in which its role remains unclear. We hypothesize that CXCR2 in epithelial and endothelial cells contributes to neutrophil recruitment into the lung by modifying the availability of its cognate chemokines in lung alveoli. Using conditional endothelial and epithelial CXCR2 knockout mice, we demonstrate that selective CXCR2 deletion in either compartment impairs neutrophil recruitment into the lung during bacterial pneumonia and reduces bacterial clearance. We show that CXCR2 ablation in epithelial and endothelial cells compromises respective trans-epithelial and trans-endothelial transcytosis of alveolar CXCL1. Mechanistically, CXCR2-mediated CXCL1 endothelial and epithelial cell transcytosis requires the function of Bruton's tyrosine kinase in these cells. In conclusion, CXCR2 plays an important role in alveolar epithelial and endothelial cells, where it mediates cognate chemokine transcytosis, thus actively supporting their activities in neutrophil recruitment to the infected lungs.
© 2025. The Author(s).

Pulmonary fibrosis (PF) is an interstitial chronic lung disease characterized by interstitial inflammation and extracellular matrix deposition, resulting in progressive lung dysfunction and ultimate respiratory failure. However, lacking of precise and noninvasive tracers for fibrotic lesions limits timely diagnosis and treatment. Here, we identified LyP-1, a cyclic peptide, as a specific and sensitive tracer for PF detection using PET/CT imaging. FITC-LyP-1 selectively recognized fibrotic regions in bleomycin-induced PF mice, indicating its targeting capability. The colocalization of FITC-LyP-1 with extracellular collagen I within the fibrotic lesions validated its specificity, and further analysis revealed several potential target molecules. In the in vivo application studies, radiolabeled [68Ga]Ga-LyP-1 showed significantly increased lung uptake in PF mice, specifically enriching fibrotic regions on PET/CT imaging. Notably, compared to CT imaging that showed increased mean lung density throughout the phases after bleomycin-administration, lung uptake of [68Ga]Ga-LyP-1 was only increased in the later phase, indicating that LyP-1 recognizes the fibrous changes rather than the inflammatory cells in vivo. These results suggest that the new radiotracer [68Ga]Ga-LyP-1 specifically detects the extracellular matrix in fibrotic lungs. LyP-1 shows promise as a noninvasive tracer for assessing human pulmonary fibrosis, offering potential for improved diagnostic accuracy and timely intervention.
© 2024. The Author(s).

Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.
To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint).
During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.
In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.
© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.

Aging of the brain vasculature plays a key role in the development of neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, the role of genomic instability in brain endothelial cells (EC) and its potential effect on brain homeostasis is still largely unclear. We here investigated how endothelial aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human brain ECs and an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient brain ECs displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, and higher sprouting capacities due to an underlying dysregulation of the Dll4-Notch pathway. In line, EC-KO mice showed more P21+ cells, augmented expression of angiogenic markers, and a concomitant increase in the number of brain ECs and pericytes. Moreover, EC-KO mice displayed BBB leakage and enhanced cell adhesion molecule expression accompanied by peripheral immune cell infiltration into the brain. These findings were confined to the white matter, suggesting a regional susceptibility. Collectively, our results underline the role of endothelial aging as a driver of impaired BBB function, endothelial sprouting, and increased immune cell migration into the brain, thereby contributing to impaired brain homeostasis as observed during the aging process.
© 2025. The Author(s).

Transient receptor potential vanilloid 4 (TRPV4) channels have been associated with numerous pulmonary pathologies, including hypertension, asthma, and acute lung injury. However, their role in the alveolar epithelium remains unclear. We performed impedance-based resistance measurements in primary differentiated alveolar epithelial type I (AT1) cells from wild-type (WT) and TRPV4-deficient (TRPV4-/-) C57/BL6J mice to detect changes in AT1 barrier integrity upon TRPV4 activation. Both pharmacological (GSK1016790A) and a low pH-driven activation of TRPV4 were quantified, and the downstream effects on adherens junctions were assessed through the Western blotting of epithelial cadherin (E-cadherin) protein levels. Importantly, a drop in pH caused a rapid decrease in AT1 barrier resistance and increased the formation of a ~35 kDa E-cadherin C-terminal fragment, with both effects significantly reduced in TRPV4-/- AT1 cells. Similarly, the pharmacological activation of TRPV4 in AT1 cells triggered an immediate transient loss of barrier resistance and the formation of the same E-cadherin fragment, which was again diminished by TRPV4 deficiency. Moreover, TRPV4-mediated E-cadherin cleavage was significantly reduced by GI254023X, an antagonist of a disintegrin and metalloprotease 10 (ADAM10). Our results confirm the role of TRPV4 in regulating alveolar epithelial barrier permeability and provide insight into a novel signaling pathway by which TRPV4-induced Ca2+ influx stimulates metalloprotease-driven ectodomain shedding.