Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 440

His
PDGF

cell membrane phospholipds

PIP2

PLC PLD

DAG

phosphatidic acid

PLA2 PGD2

diglyceride lipase
monoglyceride lipase

mechanical signals

COx PGF2

AA

5, 12, 15 LOx

PGG2 PGE2

endoperoxid synthetase

peroxydase

cc P450 Ox

PGH2

synthetase

12−HPETE 5−HPETE DEA TXA2

synthetase

synthetase

PGI2

5−12 HETE

LOx

LktA4

synthetase

EET dihydroxy acid

LktC4

lipoxin

LktB4

LktD4

hydrolase

LktE4

LktF4

Fig. 8.3 Arachidonic acid (AA) metabolism and stimuli (molecules, hemodynamic stresses,
pressure, and WSS, and their modulation rates; Source: [ 814 ]). Arachidonic acid is a constituent of
membrane phospholipids that is released from these phospholipids by phospholipase-A2. Many of
the lipids involved as second messengers in cell signaling pathways arise from the arachidonic
acid pathway. The 3 main AA-release pathways involve membrane-bound phospholipase-C
(PLC), phospholipase-D (PLD), and phospholipase-A2 (PLA2). The 3 main AA-metabolism
pathways include: (1) cyclooxygenase (COx) that leads to eicosanoids from prostaglandins-G2
to -H2, then, prostacyclin (PGi2) and thromboxane-A2 (TxA2), etc.; (2) lipoxygenase (LOx) that
forms hydroperoxyeicosatetraenoic acids (HPETE) and dihydroxyeicosatetraenoic acid (DEA),
converted into hydroxyeicosatetraenoic acids (HETE), leukotrienes (Lkt) and lipoxins; and
(3) cytochrome P450 epoxygenase (CyP450-Ox) that manufacture epoxyeicosatrienoic acid (EET).

Other NOx isozymes in respiratory epithelia contribute to lung development,
host defense, production of epithelial mucins, cell death, response to mechanical
stress, MMP expression, and regulation of MMP12 activity (Table 8.27 )[ 816 ].
In type-1 pneumocytes, NOx2 concentration is higher than in type-2 alveolar cells
that also produce DuOx1 enzyme. Pulmonary fibroblasts manufacture NOx1 and
NOx4 (mainly) isotypes. Vascular endothelial cells express NOx1, NOx2, NOx4,
and NOx5 isozymes. In the pulmonary vasculature, NOx subtypes are activated
by numerous stimuli (angiotensin-2, endothelin, serotonin, thrombin, thromboxane-
A2, tumor-necrosis factor-

, and mechanical forces).
Endothelial NOx activity rises in response to pulmonary ischemia and hyper-
oxia [ 816 ]. In lungs, NOx-derived ROS are involved in various types of pulmonary
diseases (Table 8.27 ).

α , transforming growth factor- β