Research Projects

*Rationale: Ambient air pollutant, particulate matter (PM2.5) penetrates deep into the lung alveoli causing alveolar epithelial cells (AECs) injury through reactive oxygen species (ROS). The impact of PM2.5 from different regions in India varies across age groups, leading to increasing evidence of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In aging AECs, with inflammation and impaired repair capacity, this injury leads to diverse lung dysfunction, accelerating lung aging and vulnerability to chronic diseases. This PM2.5-induced AEC injury affects alveolar fibroblasts differently: fibroblast inactivation can lead to COPD, while activation may result in IPF. Aging lungs also experience excessive extracellular matrix (ECM) deposition and altered tissue remodeling, changing alveolar mechanics. While existing studies mostly emphasize biochemical pathways, leaving a critical gap in understanding how age-related mechanical changes influence PM2.5-driven lung diseases. Mechanical cues are known to alter gene regulation and cell states by changing cytoskeletal and nuclear mechanics, but their role in PM2.5’s effect on AECs, especially in differentially activating alveolar fibroblasts, remains unclear. *Hypothesis: Given this background and guided by our preliminary data, here we hypothesizes that age-related changes in alveolar mechanics, specifically tissue stiffness, modulate mechanical states of AECs including cytoskeletal organization, membrane integrity, nuclear morphology and cell-ECM interactions, which all leads to differential PM2.5 uptake. The injury response of AECs, influenced by their mechanical state, results in variations in cytokine and secretory factor profiles. These differential injury responses subsequently activate resident alveolar fibroblasts in distinct ways, either promoting ECM degradation (in COPD) or excessive ECM synthesis (in IPF). Identifying key mechanoregulators of AEC injury response will enable targeted interventions to modulate fibroblast activation levels. *Approach: To test this hypothesis we will 1) develop in vitro models mimicking age-related alveolar stiffness; 2) expose PM2.5 from various Indian regions to aged AECs (induced by senescence); 3) measure PM2.5 uptake and injury responses in AECs; 4) analyze AEC mechanical states using biophysical techniques; 5) examine nuclear mechanics by analyzing nuclear morphometric, chromatin compaction and histone modifications; 6) identify key mechanotransduction pathways through immunofluorescence and transcriptomic analysis, 7) establish a 3D co-culture of AEC and fibroblasts to simulate alveolar microenvironments, characterize fibroblast activation markers upon PM2.5 exposure; and 8) modulate fibroblast activation by targeting AECs injury with small molecule and siRNAs. This will reveal how aging alveolar mechanics and PM2.5 exposure drive disease-specific mechanoregulation.