Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-11-07
2004-09-28
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C424SDIG006, C514S532000, C514S567000, C514S570000, C514S576000, C514S646000, C514S716000, C514S718000, C514S721000
Reexamination Certificate
active
06797728
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the fields of cellular biology and internal medicine and to a method of treating or preventing a respiratory distress syndrome and, more particularly, to the activation and regulation of surfactant secretion in type II alveolar pneumocytes.
BACKGROUND OF THE INVENTION
A physiologically active substance, called “pulmonary surfactant” exists in the animal lungs. Pulmonary surfactant is mainly biosynthesized in and secreted from type II epithelial cells of the alveoli and is known to be present as an internal lining of the wall of t he whole respiratory tract including the alveolar region. It is known that pulmonary surfactant reduces the surface tension of the alveoli and prevents collapse of the alveoli. The ability of surfactant to reduce surface tension means that less effort is needed to re-inflate the lungs after the alveoli are drained of air during exhalation. The less effort required, the less trauma to the lung itself in the course of normal breathing.
In addition, pulmonary surfactant plays an important role as a defense mechanism in the entire respiratory tract. It is well documented that it prevents pulmonary edema and has preventative effects on bacterial infection, viral infection, as well as on atmospheric pollutants and antigens which induce inflammation of the respiratory tract or asthmatic attacks. Pulmonary surfactant is also known to play an important role in lubricating the respiratory lumen and expelling foreign matter from the respiratory tract by activating mucociliary transport.
Pulmonary surfactant is a complex mixture of proteins and phospholipids. There are four known proteins in alveolar surfactant; SP-A, -B, -C, and -D. SP-B and -C are small, very hydrophobic proteins that interact with phospholipids to lower alveolar surface tension. SP-D is a 43 kDa apoprotein of uncertain function. Like SP-A, SP-D has collagen-like domains. SP-A is a moderately hydrophobic 29-36 kDa apo-protein. It reportedly stabilizes the phospholipid structure and promotes interactions between phospholipids. It also appears to be important in regulating surfactant secretion. These proteins, together with phospholipids, are secreted from alveolar type II pneumocytes and form the air-liquid interphase in the alveoli and comprise what is referred to herein as “alveolar surfactant”.
Because of its various physiological functions in the respiratory system, qualitative and quantitative changes of pulmonary surfactant seem to be related to the onset of or aggravation of many conditions. Accordingly, the modulation of secretion of pulmonary surfactant will allow for the treatment or prevention of various respiratory conditions, including, but not limited to, acute respiratory failure such as infant or adult respiratory distress syndrome, bronchitis, infectious disease and chronic respiratory failure.
The mechanism(s) that activate and regulate surfactant secretion are not well understood, but evidence suggests that calcium is important in signaling this process. The role of calcium signaling in the activation of surfactant secretion reflects changes in the concentration of free calcium in cytosol stores (lumenal calcium concentration, or [Ca
2+
]
l
) and is independent of the cytosolic calcium concentration ([Ca
2+
]
i
).
Surfactant secretion by type II cells is often studied in vitro, using receptor-binding secretagogues such as purines or &agr;-adrenergic agonists. (Sano, et al,
Am. J. Physiol.
253: C679-C686, 1987; Sen, et al,
Biochem. J.
298:681-687, 1994; Strayer, et al,
Exp. Cell Res.
226: 90-97, 1996; Strayer, et al,
Rec. Signal Transd.
7: 111-120, 1997). Surfactant secretion may also be activated independently of cell membrane receptors. Calcium ionophores (such as ionomycin (Io), are surfactant secretagogues that lack plasma membrane receptors. They release calcium from ER stores directly, and carry calcium from outside the cell into the cytosol. The secretagogue activity for thapsigargin (TG) also stimulates surfactant secretion. (Strayer, et al,
Rec. Signal Transd.
7: 111-120, 1997; Thastrop, et al,
Proc. Natl. Acad. Sci. USA
87: 2466-2470, 1990). Thapsigargin directly inhibits the Ca
2+
-dependent ATPase pump that maintains the calcium gradient at the ER stores, thereby acting directly on stores to increase [Ca
2+
]
i
. These secretagogues emphasize the importance of ER calcium stores in signaling surfactant secretion (Strayer, et al,
Exp. Cell Res.
226: 90-97, 1996). With or without receptor mediation, these secretagogues elicit rapid, large changes in [Ca
2+
]
i
. Calcium is released from intracellular stores, followed by influx of calcium through plasma membrane calcium channels. (Strayer, et al,
Rec. Signal Transd.
7: 111-120, 1997; Berridge, M J,
Nature,
361: 315-325, 1993). A potent surfactant secretagogue that is an exception are the phorbal esters. They stimulate surfactant secretion without altering [Ca
2+
]
i
. (Sano, et al,
Am. J. Physiol.
253: C679-C686, 1987).
One of the surfactant proteins, SP-A, decreases secretagogue-stimulated surfactant secretion. (Strayer, et al,
Exp. Cell Res
222: 681-687, 1994; Dobbs, et al,
Proc. Natl. Acad. Sci. USA
84:1010-1014, 1987; Hawgood and Shiffer,
Annu. Rev. Physiol.
53: 375-394, 1991; Rice, et al,
J. Appl. Physiol.
63: 692-698, 1987 Rooney, et al,
FASEB J.
8, 957-967, 1994). SP-A binds a type II cell membrane receptor (SPAR) to prevent the Ca
2+
release elicited by all the above secretagogues, including those acting directly on stores (Io and TG). (Strayer, et al,
Rec. Signal Transd.
7: 111-120, 1997). SP-A does not block transmembrane Ca
2+
fluxes, whether active (i.e., via voltage or other gated channels) or passive (e.g., via Io). (Strayer, et al,
Rec. Signal Transd.
7: 111-120, 1997).
Signaling Mechanisms in Surfactant Secretion
The signaling mechanisms that stimulate and inhibit surfactant secretion are not well understood. The diversity of secretagogues, some with different receptors, some without receptors, each with separate signaling pathways, greatly complicates the task of elucidating how surfactant secretion is triggered. (Chander and Fisher,
Am. J. Physiol.
258: L241-253, 1990; Rotonda, et al,
Thromb. Haemost.
78: 919-925, 1997). The nature of the signal that begins at the SP-A receptor (SPAR) and down-regulates surfactant secretion is even more obscure.
Adenosine binds A
2
purine receptors to activate adenylate cyclase via G protein-dependent pathways to produce cAMP. cAMP activates protein kinase A. Alpha-adrenergic agonists act similarly, though through different receptors. ATP binds P
2y
and P
2u
receptors to signal via G proteins to activate phospholipase C
&bgr;
(phosphoinositide-specific phospholipase C, PLC
&bgr;
). PLC
&bgr;
hydrolyzes phosphatidylinositol-3,4,5-trisphosphate to diacyl glycerol (DAG) and inositol-3,4,5-trisphosphate, both of which activate other enzymes, such as protein kinases C, phospholipase D, etc. Secretagogue-induced signaling in type II cells downstream from these points is poorly understood.
Intracellular calcium stores in different cell types possess several types of receptors that can be stimulated to cause Ca
2+
release. (Berridge, M J.
Nature
361:315-325, 1993; Mikoshiba, K.,
Curr. Opin. Neurobiol.
7:339-345, 1997). Ryanodine and IP3 receptors (IP3R) are examples of proteins that traverse the ER membrane and release Ca
2+
on binding their ligands. Calcium release (or increased [Ca
2+
]
i
) may activate tyrosine-specific protein kinases and calmodulin-dependent kinases. (Sugden, et al,
Cell. Signal.
9:337-351, 1997). Again, however, the means by which this signaling mechanism would result in surfactant secretion is unclear.
Downstream signaling that follows calcium release from stores is an area of intense investigation. In type II cells, calcium release activates cell membrane calcium channels, allowing influx of Ca
2+
. (Berridge, M J,
Nature
36
Choi Frank
Drinker Biddle & Reath LLP
Page Thurman K.
Thomas Jefferson University
LandOfFree
Use of intracellular calcium chelators to increase... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of intracellular calcium chelators to increase..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of intracellular calcium chelators to increase... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3212066