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British Journal of Healthcare and Medical Research - Vol. 11, No. 3

Publication Date: June 25, 2024

DOI:10.14738/bjhmr.113.16949.

Elawad, B. E. (2024). Microcirculation Mini Review: Loven’s Reflex Is Reproduced in The Lungs and Contributes in Pathophysiology

of High-Altitude Pulmonary Edema: A Hypothesis. British Journal of Healthcare and Medical Research, Vol - 11(3). 127-135.

Services for Science and Education – United Kingdom

Microcirculation Mini Review: Loven’s Reflex Is Reproduced in

The Lungs and Contributes in Pathophysiology of High-Altitude

Pulmonary Edema: A Hypothesis

Bahaeldean E. Elawad

Department of Physiology, Faculty of Medicine,

University of Umm-ALqura, Holy Makkah. Kingdom of Saudi Arabia

ABSTRACT

High altitude pulmonary edema is a serious potentially fatal state. This article

hypothesizes that, Loven’s reflex is reproduced in the lungs and contributes to the

pathophysiology of high-altitude pulmonary edema. In conclusion, Loven’s reflex

induces a positive feedback mechanism which exaggerates hypoxic pulmonary

vasoconstriction, elevates pulmonary arterial pressure, and promotes the

development of high-altitude pulmonary edema.

Keywords: Loven’s reflex; Hypoxic pulmonary vasoconstriction; Relatively less

pulmonary vasoconstriction; High altitude pulmonary edema.

In a healthy adult of 70-Kg body weight, total body water is about 42 liters; two thirds of which

is intracellular fluid (ICF) and one third is extracellular fluid (ECF). The two main

compartments of the ECF are the interstitial fluid (ISF), which makes up about three fourths

of the ECF, and the plasma, which makes up about one fourth of the ECF. The plasma is the

non-cellular portion of the blood that continuously and rapidly exchanges oxygen and

nutrients and waste products of metabolism with the interstitial fluid. This is the primary

function of the circulatory system. This exchange occurs at the level of microcirculation which

is in direct contact with the parenchymal cells. Thus, the viability of cells to support

homeostasis is absolutely dependent on proper function of microcirculation (1). Other

functions of the microcirculation include transport of nutrients, hormones, drugs, and

mediating the functional activity of immune system and haemostasis (2,3).

Microcirculation is the ultimate vascular network of the circulatory system. Microcirculation

consists of micro-vessels with diameter of less than 20 μm, which connect the arterial and

venous system. These micro-vessels are arterioles, capillaries, venules, and lymphatics (4).

Arterioles (5-100 μm in diameter) have thick smooth muscle lining and an endothelial lining

layer. Arterioles give rise directly to capillaries (5-10 μm in diameter) or, in some tissues, to

metarterioles (10-20 μm in diameter), which then give rise to capillaries. Metarterioles can

bypass the capillaries and connect directly with venules. Arterioles that give rise directly to

capillaries (terminal arterioles) are the primary determinant of blood flow through these

capillaries; by constriction or dilatation. The capillaries form an interconnecting network of

tubes with an average length of 0.5-1 mm.

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British Journal of Healthcare and Medical Research (BJHMR) Vol 11, Issue 03, June-2024

Services for Science and Education – United Kingdom

Metarterioles are thoroughfare channels that link arterioles and capillaries. Precapillary

sphincters are small cuffs of smooth muscles at the metarerioles, from which blood flows

through the capillary channel. This flow is known as nutrient flow, since it is responsible for

the primary exchange function of microcirculation. In some parts of microcirculation, blood

flow bypasses the capillary bed, moves through an anatomical arterio-venous shunt which

directly connects the arteriole with the venule. This type of blood flow is known as non- nutrient flow, because it doesn’t allow for nutrient exchange. Such non-nutrient channels are

common in the skin and are important in terms of heat exchange and heat regulation (5).

Exchange between intravascular and ISF was laid down by Ernest Starling in1896. Starling’s

hypothesis states that fluid movement due to filtration across the wall of the capillary is

dependent on the balance between the hydrostatic pressure gradient and the oncotic pressure

gradient across the capillary (6). There are four Starling’s forces determine fluid filtration

through the capillary membrane, these are: capillary hydrostatic pressure (Pc), interstitial

hydrostatic pressure (Pi), plasma colloid osmotic pressure (πc), and interstitial colloid osmotic

pressure (πi). Pc forces fluid outward through the capillary membrane to the interstitium; it is

also known as capillary filtration pressure. In systemic capillaries, Pc falls gradually from

beginning to the end of capillary (7).

Pi can be negative or positive. In organs such as the kidneys, brain, and skeletal muscles which

are encased in a tough fibrous capsule, the Pi is positive, thereby opposing filtration of the

fluid out of capillaries. In the skin which is exposed to atmospheric pressure, the Pi is several

mm Hg less than the Pc. Negative Pi pressure increases the outward forces that pull fluid out

of the capillary into the interstitium. This explains both edema at hot weather and the physical

loss of heat by radiation through ISF.

Interstitial space represents 1/6 of the body. It is supported by collagen and elastic fibers and

filled with proteoglycan molecules that combine with each other to form a tissue gel. This

tissue gel acts like sponge to entrap the ISF and provide even distribution to all cells, even

those distant from the capillaries. Although most of the fluid is entrapped in the tissue gel,

small trickles of free fluid develop between the proteoglycan molecules. Normally only small

amount of free fluid is present.

πc which averages about 28 mm Hg. Colloid solution is one in which there are evenly dispersed

particles. It tends to cause osmosis of the fluid inward through the capillary membrane. The

proteins are the only dissolved substances in the plasma that do not readily pass through the

capillary membrane. These substances exert an osmotic pressure referred to as the colloid

osmotic pressure. It reflects the osmotic effect of plasma proteins in drawing fluid into the

capillary. The term colloid osmotic pressure is used to differentiate the osmotic effect of the

particles in a colloidal solution from those of the dissolved crystalloids such as sodium. The

normal concentration of plasma proteins averages about 7.3 g/dl. About 19 mm Hg of the

colloid osmotic pressure is due to the dissolved protein, but an additional 9 mm Hg is due to

the positively charged cations, mainly sodium ions, that bind to the negatively charged plasma

proteins. This is called the Donnan equilibrium effect. About 80% of the total colloidal osmotic

pressure of the plasma results from the albumin fraction, 20% from the globulin, and only a

tiny amount from the fibrinogen. One gram of albumin (MW of 69000) contains almost six

times as many molecules as one gram of fibrinogen (MW of 420000) and two times of globulin

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129

Elawad, B. E. (2024). Microcirculation Mini Review: Loven’s Reflex Is Reproduced in The Lungs and Contributes in Pathophysiology of High-Altitude

Pulmonary Edema: A Hypothesis. British Journal of Healthcare and Medical Research, Vol - 11(3). 127-135.

URL: http://dx.doi.org/10.14738/bjhmr.113.16949.

(MW of 140000). Osmotic pressure represents the mechanical pressure or force that would

be needed to oppose the osmotic movement of water.

Not all of the protein present is effective in retaining water, so the effective capillary oncotic

pressure is lower than the measured oncotic pressure. Thus, Staverman’s osmotic reflection

coefficient is used to correct the magnitude of the measured oncotic pressure gradient (8).

Reflection coefficient is the relative impediment to the passage of a substance through a

capillary membrane. The reflection coefficient for water is zero and that of albumin (to which

the endothelium is essentially impermeable) is 1. Filterable solutes have reflection coefficient

between zero and 1. In addition different tissues have different membrane reflection

coefficient. For example, cerebrospinal fluid and the glomerular filtrate have very low protein

concentration and the reflection coefficient for protein in these capillaries is close to 1. On the

other hand, proteins cross the wall of hepatic sinusoids relatively easily and the protein

concentration in interstitial space is very high. The reflection coefficient in sinusoids is low.

The reflection coefficient in pulmonary capillaries is intermediate in value, about 0.5

With regard to systemic capillaries, it is the number, not the size, of the particles in solution

that controls the osmotic pressure.

πi tends to cause osmosis of fluid outward through the capillary membrane.

The balance of these forces (determinants of capillary filtration) allows for estimation of

effective filtration pressure (EFP) which is the net driving pressure across capillary

membrane. EFP is the difference between hydrostatic pressure gradient, which tends to push

fluid outward into interstitium, and oncotic pressure gradient, which tends to draw the fluid

into capillary (9,10).

EFP = {(Pc – Pi) – Ơ (πc – πi)}

State of equilibrium exists as long as equal amounts of fluid enter and leave the interstitial

space. This is not the case with the effect of the above mentioned four forces. Normally, slightly

more fluid leaves the capillary than can be reabsorbed. The lymphatic system represents an

accessory system that removes excess fluid, osmotically active proteins, and large particles

from the interstitial space back to the circulation. These proteins have no other way to be

returned to the plasma (11).

The removal of proteins from the interstitial space is an essential function, without which

death would occur in about 24 hours (12). The lymphatic system also returns lipids and

metabolic waste from interstitium to the circulation. The lymphatic system is composed of

lymphatic vessels (thoracic duct is the largest lymphatic vessel), lymph nodes, and lymphoid

tissues. The terminal lymph vessels are closed-end network of lymph capillaries. These lymph

capillaries resemble the blood capillaries, with two important differences: tight junctions are

not present between endothelial cells, and fine filaments anchor the lymph vessels to the

surrounding connective tissue. With the aid of intermittent muscle contraction and an

extensive system of one-way valves, these lymph vessels return the plasma capillary filtrate

to the circulation. They drain into large vessels that finally enter the right and left subclavian