Primary blast lung injury (PBLI) is a common cause of casualties in wars, terrorist attacks, and explosions. It can exist in the absence of any other outward signs of trauma, and further develop into acute lung injury (ALI) or a more severe acute respiratory distress syndrome (ARDS). The pathogenesis of PBLI at the cellular and molecular level has not been clear. Damage-associated molecular pattern (DAMP) is a general term for endogenous danger signals released by the body after injury, including intracellular protein molecules (HMGB1, histones, s100s, heat shock proteins, eCIRP, etc.), secretory protein factors (IL-1β, IL-6, IL-10, TNF-α, VEGF, complements, etc.), purines and pyrimidines and their derived degradation products (nucleic acids, ATP, ADP, UDPG, uric acid, etc.), and extracellular matrix components (hyaluronic acid, fibronectin, heparin sulfate, biglycan, etc.). DAMPs can be detected by multiple receptors including pattern recognition receptors (PRRs). The study of DAMPs and their related signaling pathways, such as the mtDNA-triggered cGAS-YAP pathway, contributes to revealing the molecular mechanism of PBLI, and provides new therapeutic targets for controlling inflammatory diseases and alleviating their symptoms. In this review, we focus on the recent progress of research on DAMPs and their signaling pathways, as well as the potential therapeutic targets and future research directions in PBLI.

Repetitive low-level blast (rLLB) exposure is a potential risk factor for the health of soldiers or workers who are exposed to it as an occupational characteristic. Alveolar macrophages (AMs) are susceptible to external blast waves and produce pro-inflammatory or anti-inflammatory effects. However, the effect of rLLB exposure on AMs is still unclear. Here, we generated rLLB waves through a miniature manual Reddy-tube and explored their effects on MH-S cell morphology, phenotype transformation, oxidative stress status, and apoptosis by immunofluorescence, real-time quantitative PCR (qPCR), western blotting (WB) and flow cytometry. Ipatasertib (GDC-0068) or PDTC was used to verify the role of the Akt/NF-κB signaling pathway in these processes. Results showed that rLLB treatment could cause morphological irregularities and cytoskeletal disorders in MH-S cells and promote their polarization to the M1 phenotype by increasing iNOS, CD86 and IL-6 expression. The molecular mechanism is through the Akt/NF-κB signaling pathway. Moreover, we found reactive oxygen species (ROS) burst, Ca²⁺ accumulation, mitochondrial membrane potential reduction, and early apoptosis of MH-S cells. Taken together, our findings suggest rLLB exposure may cause M1 polarization and early apoptosis of AMs. Fortunately, it is blocked by specific inhibitors GDC-0068 or PDTC. This study provides a new treatment strategy for preventing and alleviating health damage in the occupational population caused by rLLB exposure.