**3. Hematopoietic origin, differentiation/maturation of neutrophils**

Neutrophil biogenesis occurs in the bone marrow from an undifferentiated hematopoietic stem cell. Regulation of transcription factors through cytokine and growth factor signaling dictates neutrophil differentiation, a process called granulopoiesis. Granulopoiesis is the successive differentiation of a pluripotent hematopoietic stem cell, to a multipotent commit‐ ted myeloid progenitor cell (myeloblast), to a bipotent granulocyte-macrophage progenitor cell (metamyelocyte) and finally to a unipotent committed granulocyte. The final stage of PMN maturation, or terminal granulopoiesis, is characterized morphologically by the ap‐ pearance of a multi-lobed granulated nucleus. On a molecular level, granule protein synthe‐ sis and granule packaging mark neutrophil maturation. These granules and their cargo proteins are among the primary weapons in neutrophils' antimicrobial arsenal. [6]-[8]Syn‐ thesis of granules and granule proteins progresses concurrently with granulopoiesis. Gran‐ ules are traditionally classified as primary, secondary and tertiary according to the stage of differentiation during which they are formed. This is important because the granules formed at different stages of differentiation exhibit drastically different protein cargo and thus play different roles in the immune and inflammatory response. [9]The array of neutro‐ philic granule cargo might include myeloperoxidase, lactoferrin, haptoglobin and alpha-1 antitrypsin. [10] Specific granule proteins and their respective roles in neutrophilic lung disease will be addressed below.
