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The alveolar epithelium serves as a barrier to the entry of potential respiratory pathogens. Alveolar Type II (TII) cells have immunomodulatory functions, butwhether Type I (TI) cells, which comprise approximately 95% of the alveolar epithelium, also play a role in immunity is unknown. Because the renin-angiotensin system (RAS) is emerging as an important mediator of inflammation, and angiotensin-converting enzyme 2 (ACE2), an element of the RAS, has been implicated in lung injury,wehypothesizethat TI cells canproducecytokines in responseto LPS stimulation, and that this inflammation can be modulated by the RAS. Alveolar TI cells were isolated from adult Sprague-Dawley rat lungs that had been injured with an intratracheal instillation of LPS. PCRwas performedtodeterminewhetherTI cellsexpressed transcripts for TNF-a, IL-6,or IL-1b at baseline and after lung injury. Immunocytochemical and protein analysis detected angiotensin II (Ang II) and ACE2, aswell as angiotensin Type 1 receptor (AT1R) and Type 2 receptor (AT2R), in TI cells. To separate cell-specific responses, primary TI cells were isolated, cultured, and exposed to LPS, Ang II, or specific inhibitors of AT1R or AT2R. Cytokine production was assayed by ELISA. LPS stimulated the production of all cytokines, whereas ACE2 and losartan, anAT1Rinhibitor, blocked elementsof the LPS-induced cytokine response. Primary TI cells produce cytokines when treated with LPS, contain important components of the RAS, and can modulate LPSinduced cytokine production via the RAS, suggesting a role for TI cells in the innate immune response of the lung.
Keywords: cytokines; alveolar Type I cells; angiotensin Type 1 receptor; angiotensin-converting enzyme 2; lipopolysaccharide
The alveolar epithelium serves as an interface between an organismand the environment, providing a tight barrier that permits gas exchange but inhibits the entry of respiratory pathogens. The area of the interface is large, measuring approximately 100-150 m2 in the human lung (1), and is primarily comprised of two different cell types: alveolar Type I (TI) and Type II (TII) cells. TII cells, which cover 2-5%of the internal surface area of the lung, are cuboidal, with diameters of approximately 10 mm. TII cells are considered defenders of the alveolus because they produce and secrete surfactant, which aids in the opsonization of bacteria (2). They also release cytokines and chemotactic factors that facilitate the recruitment of inflammatory cells to sites of alveolar injury (3, 4). In contrast,...